Pharmacokinetic drug intraction

8/9/2019 Pharmacokinetic drug intraction

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PHARMACOKINETICPHARMACOKINETIC

DRUG INTERACTIONSDRUG INTERACTIONS


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DRUGS REMOVED FROM THE MARKETDRUGS REMOVED FROM THE MARKET

DURING THE 1990sDURING THE 1990s

DRUG CATEGORY REASON

Astemizole antihistamine serious metabolic

drug intxns

Bromfenac analgesic hepatotoxicity

Dexfenfluramine anorectic cardiovascular toxFelbamate anticonvulsant aplastic anemia

Flosequinan vasodilator increased mortality

Grepafloxacin antibiotic proarrhythmic

Mibefradil Ca channel blocker serious drug intxnsTemafloxacin antibiotic severe ADR

Terfenadine antihistamine serious drug intxn

Travafloxacin antibiotic hepatotoxicity

Source:J Clin Pharmacol40:1093, 2000


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I. GENERAL CONSIDERATIONSI. GENERAL CONSIDERATIONS

A. CONCEPT OF A THERAPEUTIC WINDOWA. CONCEPT OF A THERAPEUTIC WINDOW

ToxicityDesired

log Concentration

Probability o f

Response


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B. EPIDEMIOLOGICAL CONSIDERATIONSB. EPIDEMIOLOGICAL CONSIDERATIONS

HOSPITALIZED PATIENTS EXPERIENCING ANHOSPITALIZED PATIENTS EXPERIENCING ANADVERSE REACTIONADVERSE REACTION

Drug Class % Pts with Reaction

Antihypertensives 12

Anticoagulants 11Antimicrobials 6

Antiarrhythmics 4

Antiinflammatory 3

Diuretics 3Analgesics 2

Data from: May FE et,al. Drug interactions and multiple drug administration. Clin

Pharmacol Ther22:323, 1977.


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Effect of the Number of Drugs a Patient Receives onEffect of the Number of Drugs a Patient Receives onthe Frequency of Adverse Drug Reactionsthe Frequency of Adverse Drug Reactions

Number Antihypertensives Anticoagulants

0-5 9 7

6-10 9 811-15 18 15

16-20 23 18

Data from: May FE et,al. Drug interactions and multiple drug administration. Clin

Pharmacol Ther22:323, 1977.


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Prospective study of 237 patients treated with warfarinProspective study of 237 patients treated with warfarinanalyzed for determination of whether or not a druganalyzed for determination of whether or not a drug

interaction occurred with concurrent chloral hydrateinteraction occurred with concurrent chloral hydrate

All patients who received chloral hydrate 237

during warfarin therapy

Those patients who received chloral hydrate

for at least 3 consecutive days 69

Impossible to evaluate (unstable/change therapy) 28

Potentiation of anticoagulant action 22No observable interaction 19

Data from: Koch-Weser J. Hemorrhagic reactions and drug interactions in 500 warfarin

treated patients. Clin Pharmacol Ther14:139-146, 1973.


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C. TYPE OF INTERACTIONC. TYPE OF INTERACTION

UnidirectionalUnidirectional

A B

BidirectionalBidirectional

A B


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D. CLASSIFICATION OF MECHANISMD. CLASSIFICATION OF MECHANISM

ALTERATIONS IN ABSORPTIONALTERATIONS IN ABSORPTIONComplexation/ChelationComplexation/Chelation

Altered GI TransitAltered GI Transit

Example: anticholinergics + acetaminophenExample: anticholinergics + acetaminophen

Impact: delay in absorption of acetaminophenImpact: delay in absorption of acetaminophen


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ALTERATIONS IN ABSORPTIONALTERATIONS IN ABSORPTIONComplexation/ChelationComplexation/Chelation

Altered GI TransitAltered GI Transit

Altered Gastric pHAltered Gastric pH

Example: H-2 blockers + ketoconazoleExample: H-2 blockers + ketoconazole

Impact: dissolution of ketoconazole isImpact: dissolution of ketoconazole isdecreased, resulting in reduceddecreased, resulting in reduced

absorptionabsorption


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ALTERATIONS IN ABSORPTIONALTERATIONS IN ABSORPTIONALTERATIONS IN HEPATIC METABOLISMALTERATIONS IN HEPATIC METABOLISM

Induction of MetabolismInduction of Metabolism

Example: phenobarbital + warfarinExample: phenobarbital + warfarin

Impact: phenobarbital increases theImpact: phenobarbital increases the

metabolism of warfarin, resulting inmetabolism of warfarin, resulting in

reduced anticoagulationreduced anticoagulation


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Induction of MetabolismInduction of Metabolism

Inhibition of MetabolismInhibition of Metabolism

Example: cimetidine + theophyllineExample: cimetidine + theophylline

Impact: cimetidine reduces the clearanceImpact: cimetidine reduces the clearanceof theophylline causing an increase inof theophylline causing an increase in

adverse effectsadverse effects


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ALTERATIONS IN RENAL CLEARANCEALTERATIONS IN RENAL CLEARANCE

Increase in Renal Blood FlowIncrease in Renal Blood Flow

Example: hydralazine + digoxinExample: hydralazine + digoxin

Impact: hydralazine increases the renalImpact: hydralazine increases the renal

clearance of digoxinclearance of digoxin


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Inhibition of Active Tubular SecretionInhibition of Active Tubular Secretion

Example: probenecid + penicillinExample: probenecid + penicillin

Impact: probenecid prolongs the half-lifeImpact: probenecid prolongs the half-life

of penicillin, allowing single dose therapyof penicillin, allowing single dose therapy


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Inhibition of Active Tubular SecretionInhibition of Active Tubular Secretion

Alterations in Tubular ReabsorptionAlterations in Tubular Reabsorption

Example: antacids + aspirinExample: antacids + aspirin

Impact: antacids reduce the tubularImpact: antacids reduce the tubularreabsorption of salicylate via an increasereabsorption of salicylate via an increase

in urine pHin urine pH


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ALTERATIONS IN PLASMA PROTEINALTERATIONS IN PLASMA PROTEIN

BINDINGBINDING

Example: phenytoin + valproic acidExample: phenytoin + valproic acid

Impact: protein binding of valproic acid isImpact: protein binding of valproic acid is

reduced and total Css decreasedreduced and total Css decreased


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COMPOUNDS DEMONSTRATEDCOMPOUNDS DEMONSTRATED

TO BIND WITH IRONTO BIND WITH IRONACETAMINOPHENACETAMINOPHEN MINOXIDILMINOXIDIL

AMPICILLINAMPICILLIN NALIDIXI ACIDNALIDIXI ACID

CAPTOPRILCAPTOPRIL NORFLOXACINNORFLOXACIN

CARBIDOPACARBIDOPA PENICILLAMINEPENICILLAMINE

CIPROFLOXACINCIPROFLOXACIN RIFAMPINRIFAMPIN

ETHAMBUTOLETHAMBUTOL TETRACYCLINETETRACYCLINE

FOLIC ACIDFOLIC ACID THYROXINETHYROXINE

INDOMETHACININDOMETHACIN SALICYLIC ACIDSALICYLIC ACIDLEVODOPALEVODOPA

METHYLDOPAMETHYLDOPA


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B. Mediated by alterations in gastric emptyingB. Mediated by alterations in gastric emptying

or gastrointestinal transitor gastrointestinal transit

1

2

3

4

5

6

7

8

9

10

11

Fasting Fed

GRT

(hr)

Effect of food onEffect of food on

gastric residence timegastric residence time

(GRT) of the(GRT) of the

Heidelberg capsuleHeidelberg capsule

administered toadministered tohealthy male (circles)healthy male (circles)

and female (squares).and female (squares).Reproduced from: MojaverianReproduced from: Mojaverian

P et al. Effect of food on theP et al. Effect of food on the

absorption of enteric coatedabsorption of enteric coated

aspirin: Correlation withaspirin: Correlation with

gastric residence time.gastric residence time. ClinClin

Pharmacol TherPharmacol Ther 41:11-17,41:11-17,

1987.1987.


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Reproduced from: Rowland M,Tozer TN.Reproduced from: Rowland M,Tozer TN. Clinical Pharmacokinetics Concepts and ApplicationsClinical Pharmacokinetics Concepts and Applications, 3, 3rdrd edition,edition,

1995, p.2711995, p.271


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Effect of sumatriptan on acetaminophenEffect of sumatriptan on acetaminophen

absorption in patients with migrainesabsorption in patients with migraines

ParameterParameter APAP aloneAPAP alone with Sumatriptan p valuewith Sumatriptan p value

CCmaxmax (mg/L)(mg/L) 36.3 (10.9)36.3 (10.9) 18.3 (6.7)18.3 (6.7) 0.0010.001

ttmaxmax

(hr)(hr) 1.4 (0.4)1.4 (0.4) 2.7 (1.0)2.7 (1.0) 0.0010.001

tt1/21/2 (hr)(hr) 2.3 (0.7)2.3 (0.7) 3.0 (1.4)3.0 (1.4) NSNS

AUCAUC0-1.50-1.5 26.9 (9.5) 11.8 (3.7)26.9 (9.5) 11.8 (3.7) 0.0010.001

AUCAUC0-30-3 62.3 (14) 33.1 (12.9)62.3 (14) 33.1 (12.9) 0.0010.001

AUCAUC0-80-8 109 (37) 78.8 (31.3)109 (37) 78.8 (31.3) NSNS

Data from: Rani PU, et al. Sumatriptan delays paracetamolData from: Rani PU, et al. Sumatriptan delays paracetamol

absorption in migraine patients.absorption in migraine patients. Clin PharmacokinetClin Pharmacokinet11:300-11:300-

304, 1996.304, 1996.


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III. ALTERATIONS IN DRUG METABOLISMIII. ALTERATIONS IN DRUG METABOLISM

A. InductionA. Induction

int

int

int

uub

O

uubH

uubH

H

CLf

DoseF

AUC

CLfQ

CLfQCL

=

+

=


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Effect of phenobarbital (60 mg qd) on dicumarol plasma concentrations andEffect of phenobarbital (60 mg qd) on dicumarol plasma concentrations and

prothrombin time.prothrombin time. From: Cucinell SA, et al. Lowering effect of phenobarbital on plasma levelsFrom: Cucinell SA, et al. Lowering effect of phenobarbital on plasma levels

of dicumarol and diphenylhydantion.of dicumarol and diphenylhydantion. Clinical Pharmacology & TherapeuticsClinical Pharmacology & Therapeutics 6:420-429, 1965.6:420-429, 1965.


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Reproduced from: Twum-Barima Y, Carruthers SG. Quinidine-rifampin interaction.Reproduced from: Twum-Barima Y, Carruthers SG. Quinidine-rifampin interaction.NEJMNEJM304:1466, 1981.304:1466, 1981.


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From: Rowland M, Tozer TN. Ibid. p. 282.From: Rowland M, Tozer TN. Ibid. p. 282.


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Effect of cimetidine on the clearance on diazepam (D),Effect of cimetidine on the clearance on diazepam (D),

desmethyldiazepam (DZD), chlordiazepoxide (CZD) anddesmethyldiazepam (DZD), chlordiazepoxide (CZD) and

oxazepam (OXM). CZD values are x10, while OXM values areoxazepam (OXM). CZD values are x10, while OXM values are

1/10.1/10.Data from: Somogyi A, Gugler R: Drug interactions with cimetidine.Data from: Somogyi A, Gugler R: Drug interactions with cimetidine. ClinClinPharmacokinetPharmacokinet7:23, 1982.7:23, 1982.

B. InhibitionB. Inhibition


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Summary of studies assessing effect of quinolones on theophyllineSummary of studies assessing effect of quinolones on theophylline

clearance. Data from: Edwards DJ, Bowles SK, Svensson CK, Rybakclearance. Data from: Edwards DJ, Bowles SK, Svensson CK, Rybak

MJ.MJ. Clin PharmacokinetClin Pharmacokinet 15:194, 1988.15:194, 1988.


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FACTORS WHICH ALTER HEPATIC BLOOD FLOWFACTORS WHICH ALTER HEPATIC BLOOD FLOW

Increased FlowIncreased FlowGlucagonGlucagonIsoproterenolIsoproterenolPhentolaminePhentolaminePhenobarbitalPhenobarbital

PGEPGESupine postureSupine postureHigh-protein mealHigh-protein mealViral hepatitisViral hepatitis

Decreased FlowDecreased FlowPropranololPropranololNorepinephrineNorepinephrineAnestheticsAnestheticsLabetalolLabetalol

Upright postureUpright postureHypovolemiaHypovolemiaCHFCHFcirrhosiscirrhosis


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Effect of changing posture on liverEffect of changing posture on liver

blood flow and lidocaine clearanceblood flow and lidocaine clearance

ParameterParameter SupineSupine Sitting/tiltedSitting/tilted

QQHH (mL/min)(mL/min) 1100 (167)1100 (167) 765 (106)765 (106)

CL (mL/min)CL (mL/min) 602 (101) 475 (109)602 (101) 475 (109)

Data presented as mean (SD)Data presented as mean (SD)From: Feely J, et al. Effect of hypotension on liver blood flow and lidocaineFrom: Feely J, et al. Effect of hypotension on liver blood flow and lidocaine

disposition.disposition.N Engl J MedN Engl J Med307:866-869, 1982.307:866-869, 1982.


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V. ALTERATIONS IN RENAL CLEARANCEV. ALTERATIONS IN RENAL CLEARANCE

A. Renal Blood FlowA. Renal Blood Flow

Effect of vasodilators on hemodynamics, renal function and digoxin renalEffect of vasodilators on hemodynamics, renal function and digoxin renal

excretion. CI - cardiac index,; PAH -excretion. CI - cardiac index,; PAH -pp-aminohippuric acid clearance; RBF-aminohippuric acid clearance; RBF

-renal blood flow; and Dig CLr - digoxin renal clearance. Data from Cogan JJ, et-renal blood flow; and Dig CLr - digoxin renal clearance. Data from Cogan JJ, et

al.al. CirculationCirculation 64:973, 1981.64:973, 1981.


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B. Active Tubular SecretionB. Active Tubular Secretion


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B. Urine pHB. Urine pH

Renal clearance of salicylate in 11 yo child with rheumatic fever treatedRenal clearance of salicylate in 11 yo child with rheumatic fever treated

with an antacid. Data from Levy G, Lampman T, Kamath BL,with an antacid. Data from Levy G, Lampman T, Kamath BL,

Garrettson LK. Decreased serum salicylate concentrations in childrenGarrettson LK. Decreased serum salicylate concentrations in children

with rheumatic fever treated with antacid.with rheumatic fever treated with antacid. N Engl J MedN Engl J Med 293:323-325,293:323-325,

1975.1975.


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VI. ALTERATIONS IN PROTEIN BINDINGVI. ALTERATIONS IN PROTEIN BINDING

From: Rowland M, Tozer TN. Ibid, p. 274.From: Rowland M, Tozer TN. Ibid, p. 274.


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Reproduced from: Rowland M, Tozer TN.Reproduced from: Rowland M, Tozer TN.

Ibid, p. 280Ibid, p. 280


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Pharmacokinetic drug intraction