Pharmacokinetic-Pharmacodynamic Drug Interactions with Nonsteroidal Anti-Inflammatory Drugs

PHARMACOKINETIC DRUG INTERACTIONS Clin. Pharrnacokinet. 27 (6): 462·485, 1994 03 12-5963/94/00 12-0462/$ 12.0010

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Pharmacokinetic-Pharmacodynamic Drug Interactions with Nonsteroidal Anti-Inflammatory Drugs Jacobus R.BI Brouwers1 and Peter A.C.M. de Smet2

1 Department of Pharmaceutical Pharmacology and Clinical Pharmacy, Groningen Institute for Drug Studies, State University, Groningen, The Netherlands

2 Drug Information Centre, Royal Dutch Association for Advancement of Pharmacy, The Hague, The Netherlands

Contents Summary . . . . . . .. . ............. . 1. Clinical Pharmacology and Pharmacokinetics of

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) . . 2. Pharmacodynamic Interactions .......... . 3. Overview of Pharmacokinetic Interactions with NSAIDs

3.1 Absorption... . . . . . . . . . . . . 3.2 Distribution and Elimination ..... .. .

4. Drugs that Alter Pharmacokinetics of NSAIDs . 4.1 Antacids.... . . . . . . . 4.2 Sucralfate and Other Mucosal Protective Agents 4.3 Histamine H2-Receptor Antagonists 4.4 Bile Acid-Binding Resins 4.5 Probenecid . . . .. . 4.6 Steroid Hormones ... . 4.7 Miscellaneous Agents .

5. NSAIDs that Alter the Pharmacokinetics of Other Drugs 5.1 Anticoagulant Drugs . . . . . . . . 5.2 Oral Antihyperglycaemic Agents. 5.3 Anticonvulsants . 5.4 Digoxin . . . . 5.5 Lithium . . . . 5.6 Methotrexate 5.7 Cyclosporin . 5.8 Antimicrobial Agents . 5.9 Zidovudine ...... . 5.10 Miscellaneous Drugs .

6. Interactions with Other Antirheumatic Drugs . 7. Conclusion . . ........... ...... .

· 463

· 464 465

_ 467 467 467 468 468 469 470 471

· 471 · 471 · 472 · 472 · 472 · 474 · 474 · 474 · 475 · 475 · 477 · 477

478 · 478 · 479 · 481

Drug Interactions with NSAIDs

Summary The nonsteroidal anti-inflammatory drugs (NSAIDs) are very commonly prescribed, especially in the elderly population. In many countries more than 10 different NSAIDs are available. As the older pyrazole compounds like phenylbutazone, oxyphenbutazone and azapropazone are most prone to pharmacokinetic interactions, the use of these compounds should be avoided where possible.

Acidic NSAIDs interact with bile acid-binding resins, resulting in decreased concentrations of NSAIDs in the blood. In earlier reports it was suggested that the absorption of NSAIDs was affected by antacids and sucralfate. More recently, it was shown that there is delayed absorption of these drugs, but there is no difference in the extent of absorption .

Only salicylates had their urinary secretion enhanced by antacids, which increase the urinary pH to values> 7. Histamine H2-receptor antagonists can be combined safely with NSAIDs. The concomitant administration of probenecid increased the blood concentration of NSAIDs, so an enhanced anti-inflammatory effect can be expected when these 2 drugs are combined.

More importantly, NSAIDs can cause pharmacokinetic drug-drug interactions with other drugs. As can be expected, interactions with drugs that have a small therapeutic window are most likely to be of clinical significance. For example, lithium, medium to high dose methotrexate and, to a lesser extent, cyclosporin may be affected by concomitant administration of an NSAID.

Aspirin (acetylsalicylic acid) and/or pyrazoles interact with oral anticoagulants, oral antihyperglycaemic agents and the anticonvulsants phenytoin and valproic acid (sodium valproate). Elevation of blood concentrations of these agents can be potentially dangerous.

Similarly, NSAIDs interact with digoxin. This interaction is most likely to occur in the elderly, in neonates or in patients with renal impairment.

Indomethacin can influence the blood concentrations of aminoglycosides in neonates. Unfortunately, this effect seems unpredictable, so practical therapeutic recommendations cannot be made.

When NSAIDs are combined with salicylates or diflunisal, the blood concentrations of the salicylate or diflunisal may increase. However, the clinical relevance of this increase in drug concentration seems to be of minor importance. Gastrointestinal bleeding caused by NSAIDs is the most dangerous when it results from a mixed pharmacokineticlpharmacodynamic interaction; however, patients are also at risk when pharmacodynamic interactions only are involved.

463

The nonsteroidal anti-inflammatory drugs

(NSAIDs) are widely used for their analgesic and

anti-inflammatory effects . Some of the NSAIDs,

e.g. aspirin (acetylsalicylic acid) , ibuprofen and in

domethacin, are also used for the initial treatment

of fever of unknown origin and dysmenorrhoea.[ I]

Aspirin, ibuprofen and naproxen are nonprescrip

tion or over-the-counter (OTe) drugs in most coun

tries. Furthermore, it is estimated that up to 2% of

the North American population use NSAIDs on a

daily basisV] The number of NSAID users is still

growing as a result of the widespread use of acetyl

ated salicylates for the prophylaxis of thromboem

bolic complications of neurological and cardiolog

ical conditions.

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Potential drug interactions are identified in half

of the patients being treated for symptoms of arthri

tis, although the number of patients with clinical

manifestations as a result of these interactions is

small.l3] In a large study among elderly people in

Clin. Pharmacokinet. 27 (6) 1994

464

Alberta, Canada, the prescnptlOn pattern of NSAIDs was analysed. 26.7% of the Albertan population over 65 years of age received at least 1 prescription for an NSAID during the study period of 7 months. The relative frequency of drugs that may have adverse interactions with NSAIDs in elderly people was 2-fold higher in NSAID users than in the control group of non-NSAID users.l4]

From a theoretical point of view the toxicity of NSAIDs may be increased by coadministration of interacting drugs, as may the toxicity of the coadministered drug. Adverse drug reactions frequently reported for NSAIDs include dyspepsia, peptic ulceration, nausea, renal adverse effects, skin reactions, hepatic syndromes, neurological problems (e.g. headache and dizziness) and bleeding disorders VI Advanced age has emerged as one of the most striking risk factors for all of these adverse effects commonly associated with NSAID therapy.l6] This review discusses pharmacokinetic and pharmacodynamic drug interactions of NSAIDs, and updates the review previously published in the journal. l7]

1. Clinical Pharmacology and Pharmacokinetics of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

In general, the pharmacokinetic process describes the absorption, distribution and elimination of drugs. The NSAIDs differ from each other both on the basis of their pharmacokinetic and, at least to some extent, pharmacodynamic profile. Thus, the important question is: are these differences of any consequence for their clinical potential, adverse effects and interaction potential with other drugs?[8,9) The chemical classes of the different NSAIDs are shown in table I.

Despite their different chemical classes, however, many NSAIDs have the same pharmacokinetic characteristics. Most NSAIDs are rapidly and extensively absorbed after oral administration. Sometimes these agents have a low bioavailability because they are subject to considerable first-pass metabolism (e.g. aspirin). Peak serum concentrations (Cmax) of NSAIDs generally occur within 2

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Brouwers & de Smet

Table I. Chemical classes of nonsteroidal anti-inflammatory drugs (NSAIDs)

Acetic acids Indomethacin, sulindac, tolmetin

Carboxylic acids

Aspirin (acetylsalicylic acid) , carbasalate calcium, choline salicylate, diflunisal, magnesium salicylate, methylsalicylate, sodium salicylate

Enolic acids Feprazone, isoxicam, lornoxicam, mofebutazone, oxyphenbutazone, phenylbutazone, piroxicam, sudoxicam, tenoxicam

Fenamic acids

Flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid

Non·acidic compounds Bufexamac, nabumetone, nimesulide, proquazone, tenidap

Phenylacetic acids Aclofenac, diclofenac, etodolac, ketorolac

Propionic acids Carprofen, fenbufen, fenoprofen , flurbiprofen, ibuprofen, indoprofen, ketoprofen, naproxen, oxaprozin, pirprofen, suprofen, tiaprofenic acid

to 3 hours post-administration. Many NSAIDs with a short elimination half-life (t1/ 2) are commercially available in a sustained release dosage formulation so that the absorption profile and subsequently the clinical effect of the drug are prolonged. The studies referred to in this review are performed with conventional release formulations of NSAIDs, unless otherwise stated.

Only a few NSAIDs have active metabolites, e.g. fenbufen, meclofenamic acid, nabumetone, phenylbutazone and sulindac. Nearly all the NSAIDs are highly protein bound (>90% bound), and their volume of distribution (V d) is relatively small (0.1 to 0.2 Llkg). In contrast, there is a remarkable difference in the tIl2 values of the NSAIDs (table II).l9)

In most studies dealing with pharmacokinetic interactions of NSAIDs, the total plasma concentration of the drug is determined. However, the value of differences in plasma concentrations in these studies can be questioned. In terms of clinical efficacy, the free (unbound) fraction of the NSAID, differences in stereoselectivity, protein binding and



articular pharmacokinetics (for patients with rheumatoid arthritis) may be more important.[11,14] Irrespective of the tl/2 of the NSAID, the mean total concentration (protein bound plus unbound) in synovial fluid over a dosage interval is approximately 60% of the mean drug concentration in plasma. This difference may be explained by the lower levels of albumin in synovial fluid.f lO)

NSAIDs undergo hepatic elimination either through oxidation or glucuronide conjugation. As a result, drugs that alter hepatic function may alter the elimination of the NSAID. In patients with existing hepatic or renal disease with hypoalbuminaemia, it is likely that the unbound fraction of the drug would be considerably increased.

Most of the NSAIDs are excreted unchanged in urine only to a minor extent. In serious renal failure the clearance of, for example, ketoprofen, fenoprofen, naproxen and carprofen is decreased because the acyl-glucuronide metabolites of these drugs are retained and then hydrolysed back to the parent compound.fS]

2. Pharmacodynamic Interactions

The most important pharmacodynamic interactions are discussed briefly in this section.

Inhibition of renal prostaglandin synthesis by NSAIDs leading to a reduction in the renal blood flow and tubular secretion of drugs appears to be the primary mechanism for loss of blood pressure control with some antihypertensive medications, including diuretics, P-blockers and angiotensin converting enzyme (ACE) inhibitors. There seems to be some evidence that this type of interaction is least likely for sulindac, aspirip, ibuprofen and piroxicam.f 15, 16] In contrast, these effects are most pronounced with indomethacin and naproxen.[17-19]

Although only few long term studies are available, it has been shown that after long term use of the NSAID, physiological adaptation to the NSAID (e.g. ketoprofen) may occur, and blood pressure could return to baseline.[I7] NSAIDs appear to be more likely to attenuate antihypertensive drug therapy in patients with pre-existing low renal-renin activity, i.e. the elderly and Black people.


465

Table II. Mean plasma elimination half-life (t,;,) of different nonsteroidal anti-inflammatory drugs (NSAIDs)18,lO" 31

Drug t,;, of parent compound (h)

Aclofenac 1.25

Aspirin (acetylsalicylic acid) 0.25

Azapropazone 15

Diclofenac 1.1

Diflunisal 13

Etodolac 3.0 (6.5)"

Fenbufen 11

Fenoprofen 2.5

Flurbiprofen 3.8

Flufenamic acid 1.4 (9.0)"

Ibuprofen 2.1

Indomethacin 4.6

Ketoprofen 1.8

Ketorolac 3.8

Meclofenamic acid 2.0b

Mefenamic acid 3.0

Nabumetone 26b

Naproxen 13

Nimesulide 2.2

Oxaprozin 58

Oxyphenbutazone 84

Phenylbutazone 68b

Piroxicam 57

Pirprofen 3.8

Salicylate 2

Sulindac 14b

Tenoxicam 60

Tiaprofenic acid 3.0

Tolmetin 1.0 (6.8)"

a Drug has 2-phase elimination; number in parentheses refers to second-phase t,;,.

b Drug has active metabolites.

In selective cases, serum creatinine levels have been determined in patients receiving a NSAID in combination with a thiazide diuretic,l3] There are

only a few reports of loss of blood pressure control

in patients receiving NSAIDs with calcium antagonists (calcium channel blockers) or central a-agonists.f 16] However, a mixed pharmacokinetic/phar

macodynamic interaction has been reported to occur in patients receiving the calcium channel blocker felodipine and indomethacin, with a resultant increase in systolic blood pressure in nonhypertensive male volunteers.[20,21]

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466

A synergistic effect of aspirin (low dosage 325 mg/day) and verapamil on thrombocytes has been reported in case reports. The bleeding tendency increased because of enhanced effects of these agents on thrombocyte aggregation.[22]

As little as Ig of aspirin can increase bleeding time by about 60%. However, this is dependent upon the amount of aspirin esterase in red blood cells. Importantly, patients taking aspirin with anticoagulant therapy have an increased bleeding time. Aspirin dosages of 3 g/day can lead to dangerous bleeding complications as a result of pharmacokinetic interactions with the anticoagulant coumarin drugs (see also table III). Low dose aspirin (30 to 325mg) is now standard therapy in the specialities of cardiology and neurology.l27]

During acute interventions in some cardiac disorders, low dose aspirin, fibrinolytic agents and heparin are all administered simultaneously. Both theoretical considerations and clinical data suggest an increased risk of bleeding when aspirin is added to heparin and fibrinolytic therapy; in cardiology this risk is outweighed by the benefit of combined therapy. [28,29]

Low molecular weight heparins (LMWHs) or unfractionated heparin are used to prevent deep venous thrombosis in patients undergoing surgery. NSAIDs are frequently also given to these patients for the treatment of postoperative pain. There is a haemostatic interaction between heparin and NSAIDs. The haemostatic interaction between aspirin and enoxaparin or unfractionated heparin appears to be the same, although it would be expected that there would be a lower potential for aspirin to interact with a LMWH.l30J In a study of 60 consecutive patients scheduled to undergo a total hip replacement, there seemed to be a low risk of a statistically significant potentiation of the effect of the LMWH (enoxaparin 40mg twice daily) when a modest dosage of ketorolac (30 mg/day) was concomitantly administered intramuscularly.131/ Recently, the French authorities withdrew the marketing licence for ketorolac because the drug was found to be associated with an abnormally high incidence and rate of haemorrhagic events.l32] It is

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Brouwers & de Smet

Table 111. Nonsteroidal anti-inflammatory drug (NSAID) interactions with coumarins[13,23.26j The fact that a pharmacokinetic interaction

is unlikely does not mean there is no danger of bleeding. With the possible exception of nabumetone. all NSAlDs influence the thrombocyte aggregation and can enhance bleeding. especially in patients with risk factors (e.g, those who are elderly. have chronic or acute peptic ulcer or those who use corticosteroids)

NSAID Pharmacokinetic Effect on INR interaction potential with coumarins

Aspirin Likely with 1'1 (acetylsalicyclic acid) > 3 g/day

Azapropazone Likely 1'1 Diclofenac Unlikely o-ti Diflunisal Possible T Feprazone Likely 1'1 Flurbiprofen Possible i Ibuprofen Unlikely o-ti Indomethacin Possible o-ti Ketoprofen Possible o-tT Ketorolac Possible o-ti Lornoxicam Possible i Meclofenamic acid Likely i -t 1'1 Mefenamic acid Possible i Methylsalicylate (iocal) Possible i Naburnetone Unlikely 0

Naproxen Unlikely o-ti Nimesulide Possible o-tT Oxaprozin Unlikely 0

Oxyphenbutazone Likely 1'1 Phenylbutazone Likely 1'1 Piroxicam Possible o-ti Sulindac Possible i Tenoxicam Unlikely 0 Tiaprofenic acid Possible ?

Tolmetin Possible 0 -t i Abbreviation and symbols: INR = International Normalised Ratio;

i = increase; ii = considerable increase; 0 = no effect; ? = effect uncertain.

uncertain whether ketorolac per se plays a role in the high incidence of bleeding disorders; however, in the UK the datasheet for ketorolac was amended in June 1993 to advise that LMWH and ketorolac should not be administered together.

Interactions between NSAIDs and other drugs can be of a mixed pharmacokinetic and pharmacodynamic type. Many NSAIDs have an asymmetrical centre and therefore exist as an equimolar mixture of 2 enantiomers, R-(-) and S-(+). At present



most of the NSAIDs are administered in their racemic form, except for, for example, naproxen. The pharmacological activity of both enantiomers differs; in vitro studies have shown that the antiinflammatory effect of NSAIDs seems to result mainly from the activity of S-(+)-enantiomer.l 14,33]

The R-(-)-enantiomer can, however, have analgesic properties as has been shown for f1urbiprofen.l331 Warfarin also occurs in enantiomeric forms, but is administered as the racemate. Phenylbutazone inhibits the metabolism of the more potent S-isomer of warfarin, while inducing the metabolism of the less effective R-isomer. Thus, the tl/2 of S-warfarin is increased from 34 to 43 hours, while that of the R-enantiomer is decreased from 45 to 24 hours. Therefore, when phenylbutazone is coadministered with warfarin there is a more marked anticoagulant effect, without a proportional change in the total concentration of warfarin.l341

The pharmacodynamic interaction between the NSAID fenbufen and f1uoroquinolones is extremely interesting. Fluoroquinolones, in combination with certain NSAIDs, may reduce the efficacy of inhibitory [y-aminobutyric acid (GABA)Amediated] synaptic transmission in the mammalian central nervous system (eNS), leading to convulsive seizures. Whether changes in the permeability of the blood-brain barrier caused by fenbufen, thus causing changes in the distribution of fluoroquinolones, has any role in the mechanism of this interaction remains to be established. However, a pharmacodynamic interaction between these drugs seems the most plausible mechanism for this interaction.l35] A neurological effect was reported during concomitant treatment with ciprofloxacin (500mg twice daily) and naproxen (500mg twice daily) and chloroquine (250 mg/day) in a case report.l361

Immunosuppressive therapy with tacrolimus and concomitant use of ibuprofen induced acute renal failure in 2 young patients. The mechanism of this pharmacodynamic interaction remains unclearP71


3. Overview of Pharmacokinetic Interactions with NSAIDs

467

The pharmacokinetic interactions described in sections 4, 5 and 6 may result from changes in absorption, distribution and/or elimination of the NSAID. In general, changes in the extent of absorption are more relevant than those in the rate of absorption in patients being treated for chronic conditions.l341 However, for NSAIDs used for the treatment of acute pain (e.g. for headache or dysmenorrhoea), a delay in the absorption of the NSAID may be clinically significant.

3.1 Absorption

Antacids, mucoprotective agents and adsorbent antidiarrhoeal drugs may interfere with the absorption of NSAIDs. In general, the absorption of the NSAID is delayed. Time relationships, relative doses, type of formulation and the gastrointestinal contents greatly influence this physicochemical interaction. In most cases the interaction can be avoided if an interval of 2 to 3 hours is allowed between the administration of the 2 drugs.

Theoretically, drugs that enhance gastrointestinal motility (e.g. domperidone, cisapride and metoclopramide) may disturb the absorption time for NSAIDs, and therefore decrease their bioavailability. However, to date, no data are available in this regard. NSAIDs can produce mucosal damage, so changes in permeability of the gastrointestinal wall may also influence the absorption process of other drugs in a positive or negative way.l381

3.2 Distribution and Elimination

Inhibition of drug metabolism by NSAIDs plays only a minor role in their potential to cause drugdrug interactions. The agents that are most capable of inhibiting the hepatic metabolism of other drugs, such as warfarin, are phenylbutazone and oxyfenbutazone.l391 It is uncertain if other NSAIDs have any effect on the metabolism of other drugs.

Many NSAID interactions may result from protein binding displacement. For example, phenylbutazone interacts with phenytoin by displacement


468

of phenytoin from tissue binding sites, but the effect of phenylbutazone on the inhibition of the metabolism of phenytoin is of greater clinical importance. The result of the protein binding interaction is a transient decline in the total phenytoin concentration, followed by a gradual increase in phenytoin concentrations to those that are above baseline as a result of inhibition of metabolism.!38]

Many NSAIDs are acidic drugs actively transported into the renal tubular lumen. Interference with renal excretion will only be important if the fraction of the drug excreted unchanged by the kidneys is large. In general only a small fraction of NSAIDs is excreted in urine. Relatively small changes in the urine pH may alter the renal excretion of salicylates. Therefore, acidifying agents (e.g. ammonium chloride) decrease salicylate excretion, while alkalinising agents such as sodium bicarbonate increase the urinary excretion of salicylate. If high doses of salicylate are administered (>3 g/day) this mechanism may be clinically relevant.

4. Drugs that Alter Pharmacokinetics of NSAIDs

Although there is not a strong relation between blood concentrations of NSAIDs and their clinical effects, in patients with serious liver or renal disease toxicity can arise more quickly. It cannot be excluded that an increase in the concentration of NSAID in the blood can have a direct toxic effect on the kidney or liver. Furthermore, it is uncertain if high blood concentrations of NSAIDs are a relative risk for gastrointestinal bleeding. In otherwise healthy patients with pre-existing renal disease, functional volume depletion seems to be related to the incidence of toxic effects associated with NSAID therapy. Therefore, in elderly patients receiving NSAIDs, renal function should be monitored c1osely.[40] However, it seems that a decrease in the blood concentration of the NSAIDs, resulting in a lack of clinical effect, as a result of coadministration of an interacting drug is the more usual clinical occurrence.


Brouwers & de Smet

4.1 Antacids

The effects of antacids on the absorption and urinary excretion of NSAIDs have been reviewed recently.!41] High dosages of sodium bicarbonate (up to 4 g/day) are sometimes used in urology for compensating a disturbed acid excretion.

Fixed combinations of sodium bicarbonate with aspirin are commercially available. The rate of dissolution and absorption of aspirin is increased by addition of sodium bicarbonate. However, this is only clinically relevant if an immediate analgesic effect is required.!42] With high dose sodium bicarbonate or high dose aluminium-magnesium antacids the urinary pH can increase; and as a result the urinary excretion of salicylates is enhanced and blood salicylate concentrations decrease. In patients with chronic renal failure undergoing maintenance dialysis, the Cmax and time taken to achieve Cmax (tma,,;) of aspirin was reduced significantly when it was given concomitantly with aluminium-magnesium hydroxide.!43] To a lesser extent, the same effect was observed when aspirin was given with calcium carbonate.

Diflunisal absorption is increased by about 10% by the concomitant administration of magnesium hydroxide. Aluminium hydroxide decreases absorption of diflunisal by up to 26%, while aluminium-magnesium hydroxide combination antacids have no effect. [34]

A dose of 62ml of aluminium-magnesium hydroxide suspension and a single dose of ibuprofen 400mg were given to 8 volunteers in a crossover study. The high dose antacid did not alter the pharmacokinetics of ibuprofen. [44] No interaction could be determined with flurbiprofen in young (aged 21 to 31 years) and elderly (aged 58 to 77 years) volunteers after administration of aluminium-magnesium hydroxide suspension.!45]

Aluminium-magnesium hydroxide had no significant effect on the pharmacokinetics of a single 10mg dose of ketorolac.!46] Furthermore, high dose aluminium phosphate (20g) did not influence the total absorption of a single 100mg dose of ketoprofen.!47,48] Aluminium hydroxide (given as 'Aludrox' 15ml) has not been shown to affect the



total extent of drug absorption of tenoxicam given after administration of aluminium hydroxide.[49-51] Similarly, lornoxicam absorption is not affected by aluminium-magnesium hydroxide and calcium carbonate antacidsJ52.53] Magnesium hydroxide accelerated, in a dose-dependent manner, the absorption of both tolfenamic and mefenamic acid.[19] In contrast, aluminium hydroxide, either alone or with magnesium hydroxide, retarded the absorption oftolfenamic acid. Sodium bicarbonate had no significant effect.[54]

No general conclusion regarding the interaction between NSAIDs and antacids can be drawn. In studies undertaken to date, the newer NSAIDs have not been shown to have any clinical interactions with antacids. However, a difference in the rate of absorption is most often observed.

4.2 Sucralfate and Other Mucosal Protective Agents

Mucoprotective agents such as sucralfate, bismuth compounds, sulglicotide and prostaglandin analogues are used to prevent gastroirritation and gastroduodenal ulceration. Therefore, NSAIDs may be combined with mucoprotective agents to prevent the adverse gastrointestinal effects associated with NSAIDsJ55,56] Most of the studies have been performed with sucralfate. In a crossover experimental study involving 12 volunteers, single and multiple dose studies were performed to study the effect of food and sucralfate on the pharmacokinetics of naproxen and ketoprofen; the extent of absorption of the NSAIDs was unaffected by sucralfate. However, plasma concentrations of ketoprofen after single and multiple dose administration were greatly affected by food, with a decrease in bioavailability of greater than 40%J57,58]

In an earlier study, a significant increase in tmax of indomethacin occurred when the drug was given with sucralfate Ig. The tl/2 and area under the plasma concentration-time curve (AUC) of indomethacin were not significantly changed by the concomitantly administered sucralfateJ57]

When naproxen was administered with chewable sucralfate, a significant decrease in Cmax and


469

an increase in tmax values for naproxen were observed compared with values obtained when naproxen was given aloneJ59] In a study with 2 groups of 12 volunteers, no interaction was found between sucralfate and diclofenac or piroxicamJ60] Sucralfate does not alter the extent of ibuprofen absorptionJ61]

Based on these results, sucralfate has been suggested as a compressible vehicle for tablet formulations of NSAIDs (e.g. aspirin).[62] The sucralfate in the tablet matrix may act as an bioadhesive gastric protection system for the direct irritant effect of the NSAID.

Another gastroprotective system is complexation of the more lipophilic NSAIDs with ~-cyclodextrins. This has been shown to enhance the absorption of lypophilic NSAIDs, e.g. indomethacin, ketoprofen, naproxen and piroxicamJ63]

Clinical studies with other mucosal protective agents are scarce. Lornoxicam absorption was unaffected by tripotassium dicitrato bismuthate (bismuth subcitrate).[64] The bioavailability of a single dose of 100mg diclofenac sustained release formulation administered with 200mg sulglicotide was the same as that measured when diclofenac was given aloneJ65] In healthy volunteers, 200mg sulglicotide had no significant effect on the pharmacokinetics of a single 500mg dose of naproxen. For 2 other mucosal protective agents that have been developed in Japan, gefarnate and cetraxate, no interaction data are available.

Many newer NSAIDs are clinically tested in fixed doses with misoprostol , and there is no evidence of a decrease in the bioavailability of NSAIDs. In one study the pharmacokinetics of indomethacin given in combination with misoprostol were assessed. The steady-state concentration of indomethacin was 32% higher than that determined when the drug was given aloneJ56] The pharmacokinetics of diclofenac are not affected by administration of a new diclofenac/misoprostol combinationJ66] Thus, diclofenac/misoprostol may be given in a combined dosage form, with neither drug altering the pharmacokinetics of the other. Nocloprost, another cytoprotective prostaglandin-

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470

E2 analogue, did not influence the pharmacokinetic parameters of a single 50mg dose of diclofenac after repeated administration of nocloprost 200llg twice daily.!67) In 15 male volunteers (aged 21 to 25 years) a dose of 400llg of nocloprost did not influence any pharmacokinetic parameter of aspirin.[68]

Arbaprostil is an other orally active prostaglandin-E2 analogue. It inhibits gastric acid secretion and exhibits cytoprotective properties. It is used for the treatment of NSAID-related ulcers. When high dose aspirin (975mg 4 times a day for 6 days) was administered with arbaprostil (50llg) the pharmacokinetics of aspirin were not changed by arbaprostil.[69) But more data are needed to make clear conclusions on many of these interactions.!70]

The studies reviewed here show that there is a lack of significant effects of sucralfate on the absorption of the NSAIDs that are frequently used in clinical practice. Clinical data from other mucoprotective agents suggest that these agents do not usually have an effect on the absorption profile of the NSAIDs tested so far.

4.3 Histamine H2-Receptor Antagonists

NSAIDs are being prescribed increasingly with a histamine H2-receptor antagonist for the prophylaxis of drug-induced gastric or duodenal ulceration. Most studies are performed to assess the usefulness of H2-receptor antagonists in the treatment of NSAID-induced gastroduodenal lesions. The majority of the clinical studies for prophylaxis or therapy are performed with cimetidine, ranitidine or famotidine. In these studies, a positive effect (protective and/or therapeutic) on gastric and/or duodenal complaints could be detected.l71 -74] In at least 3 published review articles, interactions between NSAIDs and H2-receptor antagonists are described.l70,75,76]

Many of the published studies are of limited relevance: the studies are single-dose studies in young healthy volunteers, so it is unlikely they reflect the effect of an H2-receptor antagonist on the blood concentration of an NSAID in patients with inflammatory joint disease. Ibuprofen, flurbiprofen, sul-


Brouwers & de Smet

indac, aspirin, piroxicam and isoxicam showed a slight increase (i.e. greater than 10%, but less than 30%) in the AVC after administration of cimetidine, but not after administration of ranitidine.[70,77-79] However, the results are conflicting. In a small study in patients with joint disorders comparing the consequences of coadministration of the H2-receptor antagonists cimetidine and nizatidine with piroxicam, no clinically significant alteration in the steady-state pharmacokinetics of piroxicam occurred.[80] The AVC of salicylic acid is not altered by cimetidine or ranitidine.l42)

Only one study is published on the effect of nizatidine or cimetidine on the pharmacokinetic profile of ibuprofen.!81] Neither H2-receptor antagonist affected the pharmacokinetics of ibuprofen in humans. It has been suggested that H2-receptor antagonists may differ in their influence on the pharmacokinetics of the different R- and S-enantiomers of racemic NSAIDs, but neither cimetidine nor ranitidine interacted stereospecifically with flurbiprofen or ibuprofen.l82,83) The pharmacokinetics of indomethacin were not affected by coadministration of ranitidine after repeated oral adrninistration.!84] After single and multiple administration, cimetidine did not affect the oral pharmacokinetics of enteric-coated ketoprofen.l85)

In a study of 6 healthy volunteers, pretreatment with cimetidine (I g/day) and probenecid (I g twice daily) only altered the Cmax oftenoxicam (given as a single oral dose of 20 mg). All other pharmacokinetic parameters were not significantly affected.l86)

The effects of cimetidine, ranitidine and famotidine on the kinetics of naproxen were studied in 6 individuals. All of the H2-receptor antagonists significantly reduced the t'l2~ of naproxen by 50% from 25 to 13 hours; the initial elimination half-life (t I/ 2u) was reduced from 4 to 1.1 hours. No effect on the absorption of naproxen was observed.l87)

Cimetidine 400mg twice daily significantly increased the serum concentration, and reduced apparent oral clearance, of lornoxicam Smg twice daily in 12 healthy volunteers. However, ranitidine 150mg twice a day produced no significant changes in the pharmacokinetics of lornoxicam. [88)

Clin. Phormacokinet. 27 (6) 1994


In conclusion, the clinical relevance of the interaction between H2-receptor antagonists and NSAIDs seems unimportant. The slight increase in AUC, as shown with cimetidine may be most relevant for NSAIDs with a long tl/2 (e.g. piroxicam). Theoretically, as a result of this interaction, a lower dose of NSAIDs could be used in elderly patients when the NSAID is being given concomitantly with cimetidine.

4,4 Bile Acid-Binding Resins

In vitro studies with physiological concentrations of bile salt anions have shown that cholestyramine binds to both flufenamic acid and mefenamic acid. In vivo studies have not been performed in humans with both substances. 189J When healthy volunteers were given piroxicam with and without subsequent administration of 4g cholestyramine 3 times daily, the tl/2 of piroxicam was reduced by 40% and clearance was increased by 52% when the drugs were combined.l901 Therefore, it is recommended to separate the administration of both drugs with a time interval of at least 4 hours . No data regarding colestipol are available, but in general colestipol will bind with different drugs to a slightly lesser extent than occurs with cholestyramine.

4,5 Probenecid

Probenecid is a classical competitive inhibitor of organic acid transport in the kidney and other organs, so it can inhibit both renal and biliary excretion of NSAIDs. The decreased NSAID clearance may potentially be favourable because of increased therapeutic response. It has been postulated that inhibition of the secretion of NSAIDs results in an increased concentration of glucuronide metabolites of the NSAID in the plasma. These in turn are broken down by serum glucuronidases to release active NSAIDs.[34] Therefore, theoretically this interaction would be expected only for NSAIDs that are metabolised to glucuronides. Indeed, increases in tl/2 were shown for indomethacin[91], ketoprofen,[47] naproxen and tenoxicam.l49] But, surprisingly, probenecid (lg twice daily for 4


471

days) did not influence the pharmacokinetics of a single oral 20mg dose of tenoxicam in 6 healthy volunteers , although the Cmax was increased from 2.8 to 3.5 g/U 861

Increases of the NSAID concentration in the plasma of up to 50% have been shown.l89] In 3 volunteers, Spahn et al.[92] investigated probenecidinduced changes in the clearance of carprofen enantiomers. The plasma concentrations of S-( +)carprofen were higher than those of R-(-)-carprofen. Probenecid reduced, apparently, the total and renal clearances of both enantiomers; it also reduced the metabolism of the carprofen enantiomers to their glucuronides. Therefore, coadministration of probenecid may enhance the clinical effect of all NSAIDs that are glucuronised.

4,6 Steroid Hormones

Metandienone (methandrostenolone), an anabolic steroid, may increase plasma concentrations of oxyphenbutazone. Because oxyphenbutazone is also a metabolite of phenylbutazone, the same effect may be expected with the parent drug; oxyphenbutazone concentrations would be increased after administration of metandienone with phenylbutazone. Low dose oral contraceptives may reduce plasma diflunisal concentrations; however, the clinical importance of this interaction is not established.l93] In another study, the pharmacokinetics of oxaprozin were not different in women receiving long term conjugated estrogen treatment than those in a control group.l94J In patients given intra-articular doses of steroids (dexamethasone, methy Iprednisolone, or triamcinolone) reduced serum salicylate concentrations have been observed after administration of enteric-coated aspirin.l95]

From studies in mice it was shown that cortisone protects them from the development of salicylism,[89] but some investigators have questioned the clinical relevance of the corticosteroid-salicylate interaction.l26J From a case report in an 11-year-old child with juvenile rheumatoid arthritis, it was shown that addition of prednisone caused a significant decrease in salicylate concentration from 116 to 38 mg/L at steady -state.l961 After

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intramuscular administration of a combination of diclofenac and triamcinolone, a slight increase (about 20%) in the Cmax of diclofenac was observed. However, it was concluded that the change was due to an increased absorption rate. [97]

From the studies published so far, no final conclusion regarding the interaction between NSAIDs and steroids can be drawn; however, the interaction does not appear to have any clinical relevance. Moreover, although the interaction potential seems unimportant, one has to consider that concurrent administration of corticosteroids and NSAIDs in the elderly is a risk factor in itself for the development of upper gastrointestinal bleeding.

4.7 Miscellaneous Agents

The effect of p-adrenoreceptor-blocking agents has been shown to be influenced by several NSAIDs. For that reason, Spahn et al.[98] studied the pharmacokinetics of salicylates (3.9 g/day) administered with metoprolol. Metoprolol kinetics remained unaffected, while the Cmax of salicylic acid and aspirin was significantly higher than that achieved during the control period. These investigators concluded that metoprolol had a moderate influence on saturable salicylate metabolism. In an open, 2-period, crossover study with 18 healthy volunteers, a single oral 50mg dose of diclofenac was administered alone and again on the 7th day of administration of 50mg twice daily of the calcium channel blocker isradipine. The pharmacokinetic characteristics of diclofenac were unaltered during coadministration with isradipine.[99]

In 6 volunteers, no pharmacokinetic interaction between piroxicam and rifampicin (rifampin) could be determined) 12] The pharmacokinetic effect of paracetamol on indomethacin has been investigated in 10 volunteers. No evidence was found that paracetamol could alter the pharmacokinetics of indomethacin in humans.[IOO]

5. NSAIDs that Alter the Pharmacokinetics of Other Drugs

In general, NSAID interactions with drugs that have a narrow therapeutic window seem to be the


Brouwers & de Smet

most relevant. Therefore, most studies have been performed with this type of drug, e.g. coumarins, lithium, digoxin, methotrexate and, more recently, cyclosporin.

5.1 Anticoagulant Drugs

Unfortunately upper gastrointestinal bleeding is the most common serious complication associated with NSAID use, so an increase in the anticoagulant effect of coumarins or heparins caused by concomitant NSAID administration may be serious)40] Nearly all the NSAIDs decrease platelet function as a result of prostaglandin inhibition, contributing to their risk of gastrointestinal bleeding (see section 2). The pyrazole drugs, phenylbutazone, [10 I] oxyphenbutazone and azapropazone, [102] inhibit the metabolism of S-warfarin, thus increasing its anticoagulant effect. [to3] The other NSAIDs that are most likely to interact with warfarin are meclofenamic acid, flurbiprofen and, possibly, mefenamic acid.[23] In vitro studies have shown that most NSAIDs displace coumarin anticoagulants from their binding sites on plasma proteins. It is obvious that an increase in the unbound coumarin concentration in plasma is also likely to occur in vivo. Displacement reactions usually result in an increased fraction of unbound drug. However, the unbound concentration generally remains constant as a result of increased elimination so the long term clinical importance of this effect is of very little relevance compared with the effects of changes in hepatic metabolism.

It has been stated that some NSAIDs are less likely to interact with coumarin anticoagulants, including nabumetone, naproxen, ibuprofen, etodolac and tolmetin.[104,105] However, the available information is conflicting.[106] It cannot be excluded that advanced age and high dose NSAIDs are additional risk factors for interactions with anticoagulant drugs. Following orthopaedic surgery, a 200mg dose of sustained release ketoprofen did not cause significant displacement of the concomitantly administered oral anticoagulant from plasma proteins in 31 elderly patients; only 3 patients required their anticoagulant dosage to be adjusted)47]



In a double-blind placebo-controlled study, ketoprofen (100mg twice daily) was given for 7 days to 15 healthy volunteers stabilised on warfarin. Ketoprofen did not affect the prothrombin time and there was no clinical evidence of bleeding,1 107] although in case reports severe bleeding with combined use of warfarin and ketoprofen has been reported. I 108] In conclusion, there is no strong evidence for a pharmacokinetic and/or pharmacodynamic interaction between warfarin and ketoprof en, so this interaction is likely to be of minor clinical importance.148]

In a pharmacokinetic/pharmacodynamic study, the potential effects of multiple administration of ketorolac on racemic warfarin were studied in 12 male volunteers . Ketorolac produced no major change in the pharmacokinetics of R- and S-warfarin, nor did it alter the pharmacodynamic profile of racemic warfarin. The investigators stated that the ketorolac-warfarin interaction is unlikely to be of major clinical importance. 1109] The potential interaction between etodolac (200mg twice daily) and warfarin (20mg loading dose given on day I; 10mg given on days 2 and 3) was studied in 18 healthy individuals. When warfarin was given concomitantly with etodolac, the Cmax of total (bound + unbound) warfarin was significantly decreased by 19%, the medium total clearance was increased by 13%, while the unbound fraction tended to increase from 1.245 to 1.045%. It was concluded that etodolac does not augment the pharmacological effect of warfarin. I lOS]

The interaction between lornoxicam and warfarin was studied in 12 male volunteers. With warfarin was given with lornoxicam, the mean warfarin concentration was approximately 30% higher than when warfarin was given alone. Ravic et al. lllO] did not study the influence of lornoxicam on both warfarin stereoisomers or the displacement of warfarin from plasma protein binding sites. Therefore, conclusions on the nature of the interaction are speculative. Because lornoxicam enhanced the hypothrombinaemic effect of warfarin, it is concluded that the interaction is of moderate clinical significance.

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Nabumetone does not cause significant inhibition of platelet aggregation because it inhibits the prostaglandin synthetase-2-isoenzyme instead of prostaglandin synthetase-I-isoenzyme. Furthermore, in studies of patients and healthy volunteers stabilised on warfarin, nabumetone did not cause alterations in the prothrombin time or of the International Normalised Ratio (INR). This makes a pharmacodynamic interaction between warfarin and nabumetone uncertain,l2S]

Mean prothrombin time did not change after the administration of oxaprozin 200mg once daily for 7 days in 10 volunteers previously stabilised on warfarin. Oxaprozin did not appear to displace warfarin from its protein binding sites.llll ] Tenoxicam did not show clinically significant interactions with phenprocoumon or warfarin.149.S0, 112]

A serious interaction between tiaprofenic acid and warfarin was reported in a case report,1 113] but pharmacokinetic data regarding the interaction between tiaprofenic acid and other oral anticoagulants are lacking. Results on the influence of tolmetin on the protein binding of warfarin are conflicting. A review of the literature failed to reveal clinical studies on the interaction between tolmetin and warfarin; indeed, only case reports have been published to date,l114] In another case report, a serious interaction between warfarin and indomethacin was reported. Although pharmacokinetic data were not given, it seems most likely that this interaction was pharmacodynamic I I IS] (see also table III). The finding of Chow et al.,o 16] that topical methylsalicylate ointment can cause a potentially hazardous interaction with warfarin, is interesting. The mechanism of this interaction remains speculative. However, the explanation may be that methylsalicylate displaces warfarin from protein binding sites; resulting in a transient effect on warfarin concentrations in the plasma. 1117] The interaction potential of different NSAIDs and coumarins is given in table III.

It has to be considered that concomitant use of some H2-receptor antagonists (e.g. cimetidine) or omeprazole may increase the INR. I 118, 119] Thus, it

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is possible that these drugs may enhance the bleeding tendency of NSAIDs!

In conclusion, some of the older NSAIDs (azapropazone, feprazone, oxyphenbutazone, phenylbutazone) have an important pharmacokinetic interaction with coumarin anticoagulants. The newer NSAIDs have a low potential to cause a pharmacokinetic interaction with coumarin agents; therefore, pharmacodynamic interactions are the most prominent risk factor for bleeding disorders when these NSAIDs are given with anticoagulants.

5.2 Oral Antihyperglycaemic Agents

Only phenylbutazone, oxyphenbutazone, sulfinpyrazone and azapropazone inhibit the metabolism of antihyperglycaemic drugs of the sulphonylurea class, such as tolbutamide and glipizide. It has been shown that the t'!2 of the sulphonylureas can increase 3- to 4-fold after concomitant administration of these NSAIDs)I03] Chlorpropamide has also been shown to interact with phenylbutazone. Using data of the 1985 National Ambulatory Medical Care Survey, investigators concluded that potentially significant interactions between aspirin and both tolazamide and chlorpropamide exist)120] High dose aspirin displaces tolbutamide from its protein binding sites, but inhibition of the drug metabolism of tolbutamide may also playa role)9] Although the short term effects of aspirin on blood glucose concentrations in patients with diabetes has been described,[121] it has to be considered that deregulation of blood glucose control may be due to the underlying disease (e.g. fever) rather than the aspirin per se.

Many of the newer NSAIDs have been studied for their potential to interact with antihyperglycaemic agents. Nimesulide caused no interaction with various antihyperglycaemic sulphonylureas)13] Similarly, mofebutazone had no interaction with glibenclamide (glyburide»)122] Ketorolac did not influence the plasma protein binding of tolbutamide)461 Tenoxicam did not interact with glibornuride or glibenclamide)50]


Brouwers & de Smet

5.3 Anticonvulsants

Two anticonvulsants have been intensively studied for their potential to interact with NSAIDs: phenytoin and valproic acid (sodium valproate). Phenylbutazone, oxyphenbutazone and azapropazone inhibit the metabolism of phenytoin, thus increasing plasma phenytoin concentrations and subsequently the risk of toxicity. Additionally, these drugs may displace phenytoin from plasma proteins and increase the unbound (active) fraction of phenytoin.

Salicylates can also displace phenytoin from plasma protein, thus increasing the free fraction of phenytoin and enhancing its clearance. It has been proven that the increased phenytoin clearance may deplete plasma folate, which is required to maintain phenytoin clearance. This can result in phenytoin intoxication; however, this interaction can be reversed by supplemental administration of folic acid)17] Other NSAIDs investigated so far have only minor effects on phenytoin plasma protein binding.

The main metabolic pathway of valproic acid includes ~-oxidation; oxidation is prevented by administration of high doses of aspirin. [123] Displacement of valproic acid from binding sites by salicylates is another potential mechanism of interaction. The total effect of both mechanisms is a decrease in free valproic acid clearance of about 30% and an increase in serum free valproic acid concentrations of about 50%. Therefore, the valproic acid-aspirin interaction seems to be clinically relevant.[I 241

5.4 Digoxin

The interaction between NSAIDs and digoxin seems relevant only through the potential ability of NSAIDs to reduce renal function. Therefore, it is not a pharmacokinetic interaction, per se, but an organ-drug pharmacodynamic interaction. The kidney in the very young and very old individual seems to be the most sensitive to the toxic effect of NSAIDs. Furthermore, NSAID interactions are most relevant in patients with reduced renal function) 1251 In a recent study of patients on long term



digoxin treatment it was shown that, even without changes in renal function, digoxin concentrations increased significantly when indomethacin (50mg 3 times daily) was coadministered. In contrast, concomitant administration of ibuprofen (600mg 3 times daily) and nimesulide (lOOmg twice daily) did not cause any increase in digoxin serum concentrations.l126.127] Clinical digoxin toxicity has been reported in neonates who are concomitantly being treated with indomethacin for the treatment of persistent ductus arteriosus.l1 28]

5.5 Lithium

Most of the reports of the possible interaction between NSAIDs and lithium are case reports or small population group studies during short periods of concomitant administration. The mechanism of the interaction seems to be mainly reduction of the plasma clearance of lithium through inhibition of the synthesis of renal prostaglandins during concurrent administration of NSAIDs. Other factors (in case reports) that have contributed to toxicity are dehydration, compromised kidney function, diuretics, high dose NSAID therapy and advanced age.

Most of the work has been reviewed and studied by Ragheb.!129] Indomethacin, in a dosage of 150 mg/day, increased the lithium serum concentration by 59% in 3 patients and by 30% in 4 volunteers. In 5 healthy female volunteers with steady-state lithium concentrations, diclofenac in a dosage of 250 mg/day increased the lithium concentration by a mean of 26%. In 7 older patients (age >60 years) receiving naproxen 750 mg/day, a marked increase in lithium concentrations was reported; however, this increase was subject to considerable interindividual variation (0 to 4l.9%). Ibuprofen (1800 mg/day) increased serum lithium concentrations by an average of 34% in 9 patients, but, in common with naproxen, there was interindividual variation ranging from 12 to 66%. From many case reports it is concluded that the increase in serum lithium concentrations following administration of ibuprofen can be clinically significant in some patients. While a patient with serious renal impair-


475

ment on maintenance lithium (with stable steadystate concentrations) received 400mg of ibuprofen 4 times daily, lithium concentrations increased to within the toxic range (4.2 mmol/L).l130]

Surprisingly, aspirin in dosages ranging from 3.9 to 4.0 g/day (n = 12) did not cause any significant increase in lithium serum concentrations. There is no convincing evidence that sulindac can affect serum lithium concentrations to a degree that is clinically significant. Phenylbutazone (300 mg/day) caused only a moderate increase in lithium serum concentrations of 11 % in 5 patients, while clometacin (450 mg/day) given to 6 women increased serum lithium concentrations from an average of 0.64 to 1.01 mmollL within 6 days. Case reports have demonstrated increased lithium concentrations with concurrent use of ketoprofen, ketorolac, oxyphenbutazone, mefenamic acid and piroxicam.[ 129-133]

Therefore, most NSAIDs can increase serum lithium concentrations to potentially toxic concentrations, but the increase may be unpredictable and variable. Serum lithium concentrations and renal function should be monitored very closely in patients on concurrent lithium and NSAIDs. To prevent lithium toxicity, the dose of lithium can be reduced by 25 to 50% during concomitant administration of NSAIDs.

5.6 Methotrexate

Slow-acting antirheumatic drugs, such as methotrexate, are increasingly used in the treatment of rheumatoid arthritis.l 134] NSAIDs are, therefore, regularly coadministered with low dose methotrexate. In patients with rheumatoid arthritis, methotrexate is usually given as a single weekly oral or intramuscular dose of 5 to 20mg.! 135] Cmax values for methotrexate occur 1 to 2 hours after oral or intramuscular administration of the drug. Only 35 to 50% of circulating methotrexate is bound to albumin.[136] Methotrexate is eliminated predominantly by renal excretion and has a tl/2 of 7 to 10 hours in patients with normal renal function.

The mechanism of the interaction between methotrexate and NSAIDs involves decreased glom-


476

erular filtration of methotrexate secondary to NSAID-induced renal capillary constriction, displacement of methotrexate and 7-hydroxy-methotrexate from plasma proteins, and impairment of the hepatic metabolism of methotrexate by NSAIDsJI37) Hepatic failure, reduced kidney function, hypoalbuminuria and advanced age are likely to be other factors contributing to the interaction between methotrexate and NSAIDs, resulting in toxicityV]

Most of the reports on severe adverse effects resulting from coadministration of NSAIDs and/or salicylates with methotrexate are associated with high or moderate dosages (i.e. >20 mg/week) of methotrexate. (103) It has been suggested that the timing of methotrexate and NSAID administration is relevant for toxicity. For example, there was an increase in the concentration of methotrexate in those patients who received ketoprofen within 12 hours of administration of high dose methotrexate, while in patients who received ketoprofen 12 to 24 hours after administration of methotrexate there appeared to be no affect on the elimination of methotrexateJl38] However, it is unclear whether this is valid for low dose (i.e. <20 mg/week) methotrexate. There have been many case reports on the interaction between methotrexate and NSAIDs:[34] ketoprofen, azapropazone, phenylbutazone, diclofenac, indomethacin and naproxen. All have reported severe methotrexate adverse effects, e.g. leucopenia and thrombocytopenia. In most of the cases high doses of methotrexate were administered.

There are only a few small clinical trials that have studied the interaction between NSAID and low dose methotrexate. [139] In a comparison of 22 patients taking NSAIDs and 12 patients taking aspirin (all patients were taking methotrexate for rheumatoid arthritis), no difference in clinical adverse effects between the 2 groups was seen.

Stewart and Evans[140] studied the pharmacokinetic interaction between methotrexate 15mg (oral or intravenous) and naproxen 1000mg in 5 patients. Neither the systemic clearance of methotrexate nor the oral clearance of the drug was af-

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fected by the concomitant administration of naproxen. There was no change in bioavailability or protein binding. In another study, 15 volunteers with a diagnosis of rheumatoid arthritis were administered intravenous methotrexate lOmg either as monotherapy or after taking aspirin (3.9 g/day) for 7 days. The systemic clearance of methotrexate was significantly lower in patients receiving aspirin than it was in the control group of patients not receiving aspirin. However, the clinical relevance of the 20% reduction in methotrexate clearance has not been determinedJl40]

Skeith et al.[141] showed that 7 days' administration of flurbiprofen 300 mg/day had no effect on the pharmacokinetics of methotrexate in a study of 5 patients with rheumatoid arthritis. Similarly, ibuprofen (800mg 3 times a day for 7 days) had no effect on the pharmacokinetic profile of methotrexate (15mg intramuscularly or 20mg orally).1141] In 19 patients with rheumatoid arthritis, a single intramuscular injection of methotrexate 10mg was administered in the absence and presence of steadystate concentrations of etodolac (200mg 3 times daily). There was only a small, but significant, effect on the Cmax value when methotrexate was administered with etodolac (i.e. Cmax of methotrexate decreased from 0.59 to 0.51 IlmoIlL).[142]

Furst et al.[ 143] studied the effect of aspirin and sulindac on the pharmacokinetic profile of low dose methotrexate (10 mg/m2 intravenously). No differences in methotrexate clearance were found when methotrexate monotherapy was compared with methotrexate plus aspirin or methotrexate plus sulindac.

In animal experiments it was shown that indomethacin enhanced the toxicity and efficacy of methotrexateJ 144] A change in protein binding is a possible cause of this drug interaction, but from in vitro protein binding displacement studies it was suggested that the binding of methotrexate is not influenced by indomethacin.[ 144] This is in contrast with a study with salicylate and methotrexate; the salicylate significantly displaced methotrexate from its protein binding, increasing the unbound fraction of methotrexate by 28%.1 145) Furthermore,



renal clearance of methotrexate administered with the salicylate or ibuprofen was significantly lower than that of the control individuals. In contrast, naproxen did not change the renal clearance by methotrexate.

In 7 children with chronic inflammatory arthritis the interaction between methotrexate (5 to 8.9 mg/m2/week) and NSAIDs was studied. The mean methotrexate tl/2 was slightly, but not significantly, prolonged in children receiving concomitant NSAIDs (tolmetin, indomethacin, naproxen or aspirin).l146] In 9 children with juvenile rheumatoid arthritis taking their usual dosages of methotrexate (0.22 to 1.02 mg/kg/week) and naproxen (14.6 to 18.8 mg/kg/day), the pharmacokinetics of methotrexate (i.e. tl/2 and Vd at steady-state) were altered in 4 of the 9 children.[147]

Therefore, it seems that administration of NSAIDs with low dosage methotrexate (~20 mg/week) in patients with rheumatoid arthritis does not cause a clinically important increase in the incidence of methotrexate toxicity.[146,147] However, patients with reduced renal function may be at an additional risk of toxicity from the combination even when low doses of methotrexate are used.l148-150]

Moderate and high doses of methotrexate, as used in oncology, are prone to serious and potentially fatal toxicity when combined with NSAIDs.

5.7 Cyclosporin

Recently, cyclosporin was introduced as an effective agent in the treatment of resistant rheumatoid arthritis, but renal toxicity associated with its administration seems to be a limiting factor for its widespread use.[151] Patients with rheumatoid arthritis (and other patients) receiving cyclosporin may be at risk of accentuated nephrotoxicity when the drug is given concurrently with NSAIDs. Nearly all NSAIDs, with the possible exception ofthe prodrug, sulindac and nabumetone,l152] inhibit the synthesis of renal prostaglandins, and renal impairment and nephrotoxicity have been reported when cyclosporin is coadministered with NSAIDs.[153]

Most of the reports of toxicity associated with the use of cyclosporin in combination with NSAIDs

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are case reports, with only a few clinical studies being published on the topic. Although a clear association between enhanced renal impairment and the combined use of cyclosporin and aspirin has been demonstrated, the conclusion is that the interaction is pharmacodynamic rather than pharmacokinetic. In 24 healthy volunteers, cyclosporin 300mg was administered with or without aspirin 960mg 3 times daily.[154] A lack of pharmacokinetic interaction was conclusively shown for the rate and extent of cyclosporin and aspirin absorption and for the rate and extent of salicylic acid formation. Altman et al.l 155] studied 11 patients with rheumatoid arthritis refractory to other treatment, and concluded that after treatment with cyclosporin 5 mg/kg/day, with or without NSAIDs (naproxen or sulindac), more marked reductions in glomerular filtration rate and effective renal plasma flow occurred. Unfortunately, no pharmacokinetic data were provided in this study. In another study, no pharmacokinetic interaction was found between a single dose of cyclosporin (300mg) and diclofenac after multiple dose administration of diclofenac.l 156]

Case reports on the NSAID-cyclosporin interaction included mefenamic acid, diclofenac, sulindac, ketoprofen and piroxicam.[154-159] In many of these case reports, an elevation of cyclosporin concentrations was shown to be secondary to a decrease in renal function. Only in one case report was the interaction considered to be pharmacokinetically based. In this report it was suggested that sulindac may inhibit cytochrome P450 systems and subsequently reduce hepatic cyclosporin metabolism. [159]

In conclusion, the interaction between cyclosporin and NSAIDs may be clinically important. It appears that this interaction is of a pharmacodynamic origin.l 160- 162]

5.8 Antimicrobial Agents

Because indomethacin may be administered for pharmacological closure of ductus arteriosus in premature neonates, the effect of indomethacin on Cmax and serum trough concentrations (Cmin) for


478

gentamicin and amikacin were determined in 20 preterm infants. An increase in serum concentrations of between 17 and 48% was observed)26] However, other investigators found that indomethacin had no pronounced or prolonged effect on serum gentamicin concentrations. [163] Therefore, the relevance of the indomethacin-aminoglycoside interaction is unpredictable) 163]

Fluoroquinolones have been associated with adverse drug reactions involving the CNS (i.e. seizures). The effect is enhanced by certain NSAIDs, such as fenbufen, flurbiprofen and felbinac; however, it appears that this is predominantly a pharmacodynamic interaction. [164.165] Ketoprofen did not significantly modify the pharmacokinetic parameters of ofloxacin and pefloxacin in studies undertaken in 10 male volunteers) 166, 167]

5.9 Zidovudine

Naproxen and indomethacin are strong inhibitors of zidovudine glucuronidation; 10 to 30% inhibition of zidovudine metabolism has been shown. [168,1691 Therapeutic doses of naproxen had no significant effect on the in vivo disposition of zidovudine and its glucuronide metabolites in a study undertaken with 12 men infected with HIV.l170]

5,10 Miscellaneous Drugs

5.10.1 Acetazolamide A serious interaction between salicylate and

acetazolamide has been described in 2 elderly patients) 171] The unbound fraction of acetazolamide increased from 3.3 to 11.0% in one patient and to 30% in the other. The patients developed lethargy, incontinence and confusion as a result of the toxic effects of acetazolamide. In a small study in 4 volunteers given 6 days of oral salicylate or flurbiprofen with or without intravenous acetazolamide,II72] the AUC for acetazolamide in erythrocytes was increased by about 40% during salicylate treatment, while flurbiprofen had no effect.[I72]

5.10.2 (3-Receptor Antagonists The effects of piroxicam on the pharmacokinet

ics of both atenolol or metoprolol were studied in 6 volunteers over a period of 7 days. The AUC for

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Brouwers & de Smet

atenolol was the same as that measured when piroxicam was not being given. In the metoprolol group, the AUC and Cmax were only slightly elevated during concurrent treatment with piroxicam; however, the differences were not statistically significant. [173]

5.10.3 Chloroquine In a study in 8 volunteers, the pharmacokinetic

parameters of chloroquine were studied during concomitant administration of aspirin, paracetamol and 'Analgin' (a combination of aspirin 200mg, phenacetin 240mg, caffeine lOmg and codeine 5mg). Paracetamol and chloroquine enhanced the Cmax and AUC of chloroquine by approximately 25%)174] A patient on a combination of indomethacin and chloroquine developed serious adverse effects when ciprofloxacin was added to the treatment. I175] However, the mechanisms underlying this interaction are uncertain.

5.10.4 Cisplatin Five patients treated with cisplatin for carci

noma had pharmacokinetic studies undertaken to investigate the effect ofNSAIDs) 176] The NSAIDs studied were flufenamic acid, indomethacin, piroxicam, aspirin and sulindac. From in vitro and in vivo studies, these NSAIDs did not appear to have any affect on the pharmacokinetic profile of cisplatin. Only indomethacin caused a slight change in the free concentration of cisplatin.

5.10.5 Midazolam 20 patients undergoing surgery were treated with

0.3 mg/kg intravenous midazolam with or without I mg/kg of intravenous diclofenac to assess whether there was any interaction between these 2 agents. Although no differences in the anaesthetic characteristics of midazolam were observed, pharrnacokinetic data were not provided) 177]

5.10.6 Morphine Opioid drugs are frequently combined with

NSAIDs to enhance their analgesic potential. Six patients receiving maintenance oral morphine were concomitantly administered oral diclofenac 75mg twice daily. Diclofenac did not modify the bioavailability of morphine; therefore, it was con-

Clin. Phormacokinet, 27 (6) 1994


cluded that the combination is safe) 1781 In a single patient, severe postoperative respiratory depression was observed when intramuscular ketorolac was combined with buprenorphine.[179]

5. 70.7 Corticosteroids The effect of tenidap on the pharmacokinetics

of prednisolone in 12 healthy volunteers receiving tenidap (120 mg/day) or placebo orally for 28 days was studied. On day 21, each individual received an oral dose of prednisone 0.8 mg/kg or intravenous prednisolone 0.66 mg/kg, followed by the other steroid on day 28 (i.e. prednisone on day 21 and prednisolone on day 28 or prednisolone on day 21 and prednisone on day 28). The renal clearance of prednisolone was significantly reduced by tenidap [from 147 ml/min/1.73m2 (8.8 Llh/1.73m2) to 77 mllmin/1.73m2 (4.6 L/h/1.73m2)])180J In another study, short term treatment with indomethacin and meclofenamic acid did not alter the release of corticotrophin (adrenocorticotrophic hormone; ACTH) and cortisol either under basal or simulated conditions) 1811

5.70.8 Theophylline An enteric coated formulation of aspirin (60

mg/day) was administered to 8 elderly patients (mean age 72.5 years) receiving theophylline who had steady-state theophylline concentrations. The steady-state serum concentrations of theophylline were not altered by the concomitant administration of aspirin.l 1821

5.70.9 Metaz%ne In 6 healthy volunteers, the pharmacodynamics

and pharmacokinetics of the distal tubular diuretic metolazone was studied after administration of indomethacin or sulindac. Neither of the NSAIDs influenced the cumulative urinary excretion of metolazone, but sodium excretion was significantly depressed in the presence of indomethacin or sulindac. These findings are likely to reflect the NSAIDinduced sodium reabsorption at loci prior to the site of action of metolazone.l 183]

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6. Interactions with Other Antirheumatic Agents

479

Most of the studies on the interaction between different NSAIDs are performed with aspirin as the reference substance. Aspirin can be displaced by competitive displacement of other NSAIDs from their sites of protein binding. Plasma isoxicam concentrations were significantly decreased in 10 volunteers when aspirin 3.9g was given in combination with isoxicam 200mg.lI84,185] Aspirin 3.9 g/day significantly decreased the steady-state plasma concentration of tenoxicam 20 mg/day from 10.4 to 4.5 mg/L in 8 healthy volunteers.l49] The nature of the interaction between aspirin and other NSAIDs seems to be competitive displacement from protein binding, resulting in transient changes in plasma concentrations.

The interaction between salicylate and naproxen was studied in a double-blind crossover study in 25 patients with rheumatoid arthritis.[186] A naproxen dosage of 1500 mg/day was used while patients were on a maintenance dose of salicylate (serum salicylate concentrations between 150 and 300 mg/L resulted after administration of 45 mg/kg/day in 2 divided doses daily). The mean total naproxen clearance increased by 56% when salicylate was added to naproxen therapy; in contrast, the average Cmax of salicylate at steady-state was not changed by addition ofnaproxen . Furthermore, naproxen did not significantly increase serum salicylate clearance when salicylate was given.

In 2 different studies, the interaction between diflunisal and indomethacin were studied)187,1881 The influence of long term diflunisal treatment on different doses of indomethacin (50 to 100mg rectally) were demonstrated in 8 volunteers. Only high dose diflunisal (1500 mg/day) caused an increase in the Cmax (40%) and AUC (119%) of indomethacin given in a high dosage (100 mg/day, rectally) . After administration of lower dosages of diflunisal (500 to 1000 mg/day) in combination with indomethacin (50 to 100 mg/day) the changes in tmax were nonsignificant, but when lower doses of diflunisal were given with indomethacin 100mg the AUC was greater than control values (22 vs 13


480 Brouwers & de Smet

Table IV. Pharmacokinetic interactions between nonsteroidal anti·inflammatory drugs (NSAIDs) and other drugs

Drug NSAID(s) implicated Clinical Effect and approach to management relevance

Drugs affecting NSAIDs Antacids

Sucralfate

Salicylates

Probably all

Probably all

+

±

Enhanced excretion if antacid changes urine pH above 7. Decreased effect of aspirin (acetylsalicylic acid) or salicylate

Delayed absorption, relevant when immediate pain relief obvious. Interval of at least 2 hours between drugs

No clinical effect Histamine H2-receptor antagonists

Bile acid·binding resins

Probenecid

Probably all acid·binding NSAIDs, e.g. flufenamic acid, mefenamic acid, piroxicam

Probably all

+

±

Absorption disturbed. Allow a time interval between administration of at least 4 hours

Enhanced clinical effect, lower dose of NSAID may be used

Steroid hormones

NSAIDs affecting other drugs Oral anticoagulants

Probably all

Pyrazoles, e.g. phenylbutazone, oxyphenylbutazone, azapropazone

++

No effect determined

Enhanced bleeding (see table III), avoid combination

Oral antihyperglycaemic agents Salicylates > 3 g/day, pyrazoles ++ Enhanced effect of sulphonylurea drug, lower dosage or avoid

Anticonvulsants

Digoxin

Lithium

Methotrexate

Cyclosporin

Antimicrobial agents

Zidovudine

Other NSAIDs

Aspirin

Pyrazoles

Probably all

Probably all

Probably all

Probably all

Indomethacin

Indomethacin, naproxen

Aspirin/enolic acids

Diflunisal/indomethacin

++

++

±-7 ++

++

++

++

±

±

±

++

Valproic acid effect enhanced, lower dose or avoid coadministration

Phenytoin effect enhanced, avoid combination

Unpredictable elevation of digoxin concentrations in the elderly and neonates, avoid combination

Unpredictable increase in lithium concentrations, avoid combination

Only relevant for nonrheumatic medium or high dose methotrexate, avoid

Elevation of cyclosporin concentration, avoid

Increased aminoglycoside concentration, frequent monitoring

Slight increase of zidovudine effect, probably not clinically relevant

Decrease of 'enolic acid' NSAIDs effect

Increase of blood indomethacin concentration, increases toxicity, avoid

Symbols. + = clinical interaction likely; ++ = serious clinical interaction, avoid combination; - = no clinical interaction; ± = clinical interaction possible.

mg/L • h). eNS reactions were observed in patients with higher plasma concentration of indomethacinJl87] Van Hecken[188] found that diflunisal

500mg twice daily increased the steady-state

plasma concentration and AVe of indomethacin 50mg twice daily by 2- to 3-fold (AVe increased


from 7.7 to 14.7 mg/L. h). From most studies it appears that potentially dangerous adverse effects

of indomethacin may be enhanced by concurrent

administration of diflunisal (~1000 mg/day). In general the interaction between NSAIDs does

not seem to be clinically relevant, with the excep-

elin. Pharmacokinet. 27 (6) 1994


tion of the interaction between aspirin or diflunisal and that between aspirin and indomethacin.

7. Conclusion

The clinical relevance of the most important pharmacokinetic interactions is provided in table IV. The mechanisms of the interactions are different, but are consistent with the types of drugs studied. Interaction in the absorption process is, in general, important for NSAIDs that interact with antacids or mucosal protective drugs. In general, for NSAIDs the decrease in absorption is minor, but a delay in tmax , rather than a decrease in total AVe, is observed.

Displacement of NSAIDs from protein binding sites by other drugs may be one mechanism of pharmacokinetic interaction between NSAIDs and other drugs. However, the displacement of other drugs (e.g. methotrexate) from their protein binding sites by the NSAID seems to be more clinically important.

Because of the influence of NSAIDs on renal function, differences in the renal clearance of the NSAID per se or of the concurrent drug may be expected. The NSAIDs that alter the pharmacokinetics of other drugs are most important. In this respect, the older NSAIDs phenylbutazone, oxyphenbutazone and azapropazone have a high potential to interact with other drugs, and, therefore, other NSAIDs should be used in preference to these drugs.

The elderly, corticosteroid users and patients with a history of peptic ulcer disease are at most risk of experiencing a gastrointestinal bleed whilst receiving NSAIDs. Nabumetone seems to be a new promising NSAID, with a bleeding potential equal to the combination of ibuprofen and misoprostolJ 189)

The most potentially dangerous pharmacokinetic interactions are those that occur between NSAIDs and lithium, methotrexate (given in medium to high dosages; i.e. >20 mg/week) and cyclosporin.


481

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Correspondence and reprints: Professor Jacobus R.B.J. Brouwers, Department of Pharmaceutical Pharmacology and Clinical Pharmacy, State University Groningen, Ant. Deusinglaan 2, 9713 AW Groningen, The Netherlands.


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Pharmacokinetic-Pharmacodynamic Drug Interactions with Nonsteroidal Anti-Inflammatory Drugs