Br. J. clin. Pharmac. (1989), 28, 621-628

The effects of food on drug bioavailabilityP. A. WINSTANLEY & M. L'E. ORMEDepartment of Pharmacology and Therapeutics, University of Liverpool, Liverpool L69 3BX

Introduction

The oral administration of drugs is convenient,and linking drug doses to daily routines such asmeal times can improve compliance (Haynes etal., 1979). However, interindividual variationin drug response, particularly following oraladministration, has long been a problem. Sincethis variation can result in therapeutic failure ordrug toxicity, the 'art of bespoke prescribing'(Routledge, 1988) remains a major goal ofclinical pharmacology. In the past variation inthe composition, strength or formulation of thedrug has often been responsible for suchproblems. Nowadays, at least in the 'developedworld' (Melrose, 1982), such formulationproblems are rare, but even so dose-responserelationships still vary from patient to patient.While such variation may result from pharma-codynamic factors, as is often the case withwarfarin for example (Routledge et al., 1979),pharmacokinetic factors are also important.To produce a clinical response, a drug must

achieve an effective concentration at its siteof action, which must be maintained for anadequate length of time. For orally administeredsystemic agents, this involves the transfer of thedrug from the gut to the systemic circulation.In order to achieve this the drug must firstenter solution, and then pass into the portalblood-i.e. it must undergo absorption. Thisprocess occurs mainly by passive diffusion,though there are exceptions (for example L-dopa; Ther & Winne, 1971), and is locatedmainly in the small bowel. Following or duringabsorption, drugs are subject to the action ofenzymes prior to their distribution to the body.This may result in the partial or total biotrans-formation of the drug to pharmacologicallyactive or inactive derivatives. The main sites of'presystemic' biotransformation are the gut wall,the liver and in the case of some drugs the lungs(George & Shand, 1982). Clearly some drugsact topically upon the gastrointestinal mucosa,and do not require absorption to be effective.The therapeutic effect of such drugs e.g. chelatedbismuth preparations-can be perturbed by food,but this is not through changes in bioavailability,and is therefore not considered in this article.The term 'bioavailability' is used to describe

the fraction of drug dose which reaches thesystemic circulation unchanged, and this there-fore takes account of all the processes describedabove. Many of the factors which influencebioavailability can be changed by food, both'acutely', if a drug is taken with a meal, and'chronically', where regularly consumed fooditems influence drug disposition. The natureof these interactions is complicated, and is in-fluenced by the quantity and composition offood. It should also be noted that as well aschanging the pharmacokinetics of some drugs,food can alter their pharmacodynamic effects.This subject is not, strictly speaking, within theremit of the present article, but needs to bedealt with briefly. Perhaps the most clinicallyrelevant example concerns the sulphonylureasglibenclamide and glipizide. The bioavailabilityof neither is perturbed by food (although therate of absorption of glipizide is reduced in thenonfasted state), but their therapeutic effect issignificantly increased by taking the drugs priorto meals (Wahlin-Boll et al., 1980; Sartor et al.,1982). The exact reason for this is not clear, butmay concern food effects on pancreatic andhepatic function.

Before reviewing specific examples of effectsof food upon drug bioavailability, the theoreticalbasis for these interactions will be considered.This is not out of academic interest, but so thatthe physician can attempt to predict food/druginteractions from a few basic principles. In fact,the nature of such interactions is often so com-plex that prediction from theory is difficult, andconsequently the development of new drugsshould include assessment of food effects. None-theless, knowledge of the background theorycan prove clinically useful especially when try-ing to interpret drug failure or adverse reactionsin an individual patient.

The effects of food

Changes in gastric emptying

Few drugs are absorbed to an important degreeby the stomach, both acidic and basic drugs are

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mainly absorbed in the small bowel. However,gastric function can have major effects on boththe rate and extent of drug absorption.

In the fasting state, gastric motility is notuniform, but passes through cycles termedmigrating motor complexes (MMC). TheseMMC last about 2 h in total, but are dividedinto four phases, of which phase 3 results in thestrongest contractions but lasts only about 15min (so called housekeeper waves; Golub et al.,1986). Non nutrient liquids are moved quicklyfrom the stomach throughout the MMC, butsolids of particle size 2 mm-e.g. partly dis-solved drug-are only moved into the intestineduring the brief phase 3. Consequently, readilysoluble drugs are cleared rapidly from the fast-ing stomach to their site of absorption, but poorlysoluble drugs may take longer. Of course, themajority of drugs form suspensions or solutionsrapidly in the gastric content (British Pharma-copoeia, 1985), and are thus moved quicklyfrom the fasting stomach. There are howeversome poorly water soluble drugs (for examplegriseofulvin) whose passage into the small bowelcan be delayed because of slow dissolution andconsequent large particle size.The presence of food in the stomach changes

gastric motility to a typical postprandial pattern,during which gastric secretion and residencetime are increased. The duration of the post-prandial phase varies with the volume, physicalstructure and composition of the chyme. Gastricresidence time increases with increasing volumes,but this increase is less marked for purely liquidmeals than for those containing solids, and isincreased particularly by chyme of low pH andhigh osmolality (Walter-Sack, 1987a). Conse-quently it is usual for the RATE of absorptionof drugs to be slower when taken with mealscompared with the fasted state, and this can beimportant for drugs which need to act promnptlysuch as analgesics or sedatives. The EXTENTof absorption however is usually unchanged,and of course it is the extent rather than the rateof absorption which is a determinant of bio-availability.For some drugs, the extent of absorption can

be increased by meals. This may be becauseresidence time and fluid volume are greaterproducing better dissolution (Greenblatt et al.,1978). In particular, poorly water soluble drugs(e.g. griseofulvin, mebendazole and halofan-trine), when taken as a solid formulation maynot enter solution readily in the stomach.Administration of such drugs with very fattyfoods can increase bioavailability, possibly bysuch mechanisms as the formation of solutionsin the dietary oil. Conversely, the extent of

absorption of other compounds can be decreasedby meals. In the case of acid labile drugs, suchas penicillin and erythromycin, prolonged ex-posure to gastric acid may be the cause (Welling,1984). In the case of levodopa, absorption occursreadily in both stomach and small bowel, andfood-induced delay in gastric emptying enhancesgastric absorption of the drug. However, DOPA-decarboxylase, the enzyme responsible forlevodopa degradation, is present in gastricmucosa at high concentration, and the net effectof delayed gastric emptying is to increase thepresystemic metabolism of the drug (Bianchine& Shaw, 1976).The influence of drug formulation on inter-

actions with food can be predicted, to an extent,from knowledge of gastric function as describedabove. On the whole, solutions and suspensionsare less prone to food interactions than solidformulations. On the other hand, enteric coateddrugs often prove more susceptible, since reten-tion of the capsule in the stomach delays drugrelease.

Drug chelation

It is well known that certain drugs can interactwith food constituents, resulting in reduction indrug bioavailability. Good examples of this in-clude the interactions between first generationtetracyclines and dietary calcium (this is not somuch of a problem with doxycycline) (Siegel,1978), between penicillamine and heavy metalions (Schuna et al., 1983) and between ironformulations and tannic acid (found in tea)(Disler et al., 1975).

Changes in the activity of drug metabolisingenzymes

Food can contain, or become contaminated with,xenobiotics which affect hepatic or gut walldrug-metabolising enzymes. Brassica speciesvegetables (sprouts, cabbage, broccoli, spinachand cauliflower) have been extensively studied(Pantuck et al., 1979, 1984), and it is likely thatmany other examples await discovery world-wide. The brassica species contain enzymeinducing indoles which, if taken in sufficientquantity for long enough, can reduce the bio-availability of some drugs by increasing theirrate of metabolic clearance. Phenacetin is thedrug most extensively studied in this context.While some foods 'naturally' contain xeno-

biotics, others can become contaminated withthem. The most widely studied example of con-tamination during food preparation is charcoalbroiling of beef (Conney et al., 1976; Pantuck

Effects offood on drug bioavailability

et al., 1976), and some techniques of foodsmoking have also been studied (Santodonatoet al., 1981). These processes cause contami-nation with certain polycyclic hydrocarbonscapable of potent induction of drug metabolisingenzymes. It must be said that the quantities ofboth Brassica vegetables and charcoal-cookedbeef which the subject must consume, beforeperturbing drug disposition, is large. Themajority of patients would be unlikely to eatenough of them for long enough to see an effect.

It is likely that these fairly extensively studiedcontaminants represent only a fraction of thosewhich exist worldwide. Apart from contami-nation during cooking, foods can also acquirexenobiotics during storage. One group ofexamples are the aflatoxins which are of fungalorigin, and when consumed in sufficient quantityhave a range of effects including carcinogenicityand hepatotoxicity. In animal models certain ofthe aflatoxins have been shown to have acuteeffects on drug metabolising enzymes; forexample aflatoxin Bi lowers the activity ofUDP glucuronyl transferase and glutathione Stransferase (Rajpurohit & Krishnaswamy, 1988).Aflatoxins have been shown to contaminatemassively the diets of many 'Third World'populations (Coulter et al., 1984; Hendrickse,1985) and their effect, if any, on the bioavail-ability of drugs in man requires investigation.Furthermore, some authors have suggested thataflatoxins are causative in kwashiorkor (Hen-drickse, 1985), a syndrome which is known toperturb drug disposition (Krishnaswamy, 1983).Mention must be made of ethanol which, in

British practice, is a more commonly recognisedfood 'contaminant' with effects on drug meta-bolism. While acute ethanol ingestion can in-hibit drug metabolism (most commonly relevantin the setting of paracetamol overdose), chronicingestion is a commonly encountered cause ofmajor induction of drug metabolism. Chronicalcohol abuse may result in changes of drugdisposition not only after oral medication, butalso following the parenteral administration ofhigh clearance drugs.

This section has so far considered only theeffect of food contaminants on drug metabolisingenzymes. Contaminants apart, the compositionof the diet has effects on the activity of drugmetabolising enzymes (Walter-Sack, 1987b).A high protein diet can increase the activity ofmixed function oxidases, and this can affect thebioavailability of some drugs (e.g. propranololand theophyllines; Fagan et al., 1987). Unfor-tunately much of the world's population lacksthe chance of eating even contaminated food,and many are chronically or acutely starving.

Starvation too affects drug bioavailability(Krishnaswamy, 1983), but of course this isusually the least of the patient's problems.

Changes in splanchnic blood flow and plasmaprotein binding

The effect of food on presystemic drug clear-ance, through changes in splanchnic blood flowand plasma protein binding, has been extensivelyreviewed by Melander et al. (1988), Melander& McLean (1983) and Melander (1978). Thesemechanisms are pertinent to food-inducedchanges in the bioavailability of labetalol, pro-pranolol, metoprolol and hydralazine (seebelow).

Clinically important examples

Since food may change the bioavailability ofmany drugs, and hence influence their dose-response relationships, awareness of the moreclinically-relevant examples is of benefit to thepractising physician. The main purpose of thepresent article is to provide an up-date of thoseexamples considered to be of most clinicalrelevance (Table 1).

Food reduces bioavailability

Antimicrobial agents Food reduces the bio-availability of the non-esterified penicillins(Cronk et al., 1960), ampicillin (Jordan et al.,1981) and amoxycillin (Welling, 1977). Similarlythe absorption of many of the cephalosporins iseither delayed or reduced by food (McCrackenet al., 1978). The effect of food on the bioavail-ability of various derivatives of erythromycinhas been reviewed by Welling (1977). Briefly,the bioavailability of free erythromycin baseand that of its stearate is reduced in the non-fasted state, while that of the less water solubleand less acid-labile estolate is increased. Thebioavailability of isoniazid and rifampicin, usedextensively for the treatment of tuberculosisand multibacillary leprosy (rifampicin only) isreduced to a significant degree by concomitantfood (Melander et al., 1976; Polasa & Krish-naswamy, 1983). Rifampicin in particular is anexpensive drug for the majority of the countriesin which it is employed, and its optimal use istherefore important. Another relatively expen-sive drug employed widely both in the developedand 'third' world is the antifungal agent keto-conazole. Mannisto et al. (1982) have shownthat the AUC for ketoconazole is significantlyreduced by a high carbohydrate, low fat meal

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Table 1 Drugs whose bioavailability can be alteredto a clinically important degree by food

Drug Reference

Bioavailability decreasedPenicillin CrcAmpicillin JoriAmoxycillin WeCephalosporins McErythromycin WeTetracycline NetRifampicin PolIsoniazid MeKetoconazole MaAtenolol MeCaptopril Sin

Bioavailability increasedPropranolol MeMetoprolol MeLabetalol Da:Propafenone AxiHydralazine MeGriseofulvin PalNitrofurantoin RoMebendazole MuFlubendazole MiHalofantrine MilPhenytoin MeDicoumarol Me

onk et al. (1960)rdan et al. (1981)lling et al. (1977),Cracken et al. (1978)lling (1977)uvonen (1976)lasa & Krishnaswamy (1983)lander et al. (1976)nnisto et al. (1982)lander et al. (1979a)ghvi et al. (1982)

lander et al. (1977a)-lander et al. (1977a)neshmend & Roberts (1982)Eelson et al. (1987)lander et al. (1977b)Ima et al. (1986))senberg & Bates (1976)anst et al. (1980)ichiels et al. (1982)ilton et al. (1989)-lander et al. (1979b)vlander & Wahlin (1978)

Drugs with significant pharmacodynamic interactionwith foodGlibenclamideGlipizide

Wahlin-Boll et al. (1980)Sartor et al. (1982)

(14.38 ± 2.21 compared with 8.75 ± 1.33 ,ugml-' h; P < 0.05). The mechanism by whichthis occurs is not clear.

Antihypertensive drugs In contrast to thelipophilic ,-adrenoceptor antagonists propra-nolol and metoprolol described below, the bio-availability of the hydrophilic drug atenolol isreduced by food. Melander et al. (1979a) showedthat while food initially increases the rate ofabsorption of atenolol, its oral AUC is reducedby about 20%. Similarly, the bioavailability ofthe angiotensin converting enzyme inhibitorcaptopril appears to be reduced when takenwith food. In this example the reduction is ofthe order of 35-40% (Singhvi et al., 1982). Suchreductions in bioavailability would probably beof clinical significance over the long-term, forpatients who habitually take their medication

with meals, but in practice their short-termclinical significance is probably small.

Analgesics While the remit of the presentarticle concerns food effects on bioavailability,food more usually delays drug absorption with-out reducing the extent of absorption. This canbe of major importance to the patient however,since the onset of drug action can be delayed oreven abolished if therapeutic concentrations failto be achieved in the plasma. Consequently suchinteractions do warrant a mention. Delay of theonset of therapeutic effect is particularly impor-tant regarding analgesics. Non steroidal anti-inflammatory drugs including aspirin (Bogentoftet al., 1978), diclofenac (Willis et al., 1981) andpiroxicam (Ishizaki et al., 1979) are absorbedmore slowly with food than in the fasted state.Though their bioavailability may not be reduced,this is unlikely to reassure the patient whosemain concern is to be rid of the pain quickly.

Food increases bioavailability

Antihypertensive and antiarrhythmic drugs Theintestinal absorption of propranolol, metoprolol,labetalol and hydralazine is virtually complete,but administration of the drugs to non-fastedsubjects significantly increases their bioavail-ability (Melander et al., 1977a,b; Daneshmend& Roberts, 1982). This effect is likely to be dueto transient food-induced changes in drugabsorption rate, splanchnic blood flow, plasmaprotein binding and activity of drug metabolisingenzymes, causing temporary reduction of firstpass metabolism. These mechanisms have beenreviewed recently by Melander et al. (1988).This effect has been demonstrated particularlyconvincingly in the case of labetalol, whereDaneshmend & Roberts (1982) gave the drugto fasting and non-fasting subjects both orallyand intravenously. In this study oral bioavail-ability increased from 0.26 ± 0.03 (fasted) to0.36 ± 0.05 (non fasted; P < 0.05), while AUCfollowing i.v. dosing fell significantly as pre-dicted. In the case of these antihypertensivedrugs, the effect of food can be of clinical im-portance, and patients should be aware of theneed to take their medication at set times inrelation to meals.

Propafenone is a class IC antiarrhythmic drugsubject to extensive first-pass oxidative meta-bolism, which displays significant polymorphism-populations being phenotyped as rapid orslow metabolisers (Siddoway et al., 1983). Withthe exception of slow metabolisers who are inthe minority, food has been shown to increase

Effects offood on drug bioavailability

the bioavailability of propafenone in healthyvolunteers (Axelson et al., 1987). The maximalextent of this effect was 638%, but its clinicalimportance is not clear. Propafenone is meta-bolised to 5-hydroxy propafenone which ispharmacologically active (von Philipsborn etal., 1984), and which was not measured in thestudy of Axelson et al. (1987). Even so, untilfurther clarification is available it seems wise toadvise patients to take this drug in a constantrelationship to meals.Recommendations concerning thiazide di-

uretics and food are probably of less pressingimportance given their wide therapeutic indexand flat dose-response curve. Long term drugfailure however would clearly be important fora hypertensive patient. Unfortunately data onfood effects with hydrochlorothiazide are con-flicting. While Beerman & Groschinsky-Grind(1978) found that food enhanced the bioavail-ability of hydrochlorothiazide, more recentlyBarbhaiya et al. (1982) have found the oppositeeffect. This apparent conflict may result fromthe difference between fasting schedules em-ployed by the two studies. In clinical practice,it seems unlikely that food-induced changes inthe kinetics of this thiazide would lead to im-portant problems.

It is appropriate to mention one example ofa drug whose bioavailability is apparently un-influenced by food. Verapamil is a calciumchannel blocking agent widely used in the treat-ment of hypertension and angina (Hamman etal., 1984). It is a high clearance drug with alarge first pass effect, and on theoretical groundsone might predict that food would increase itsbioavailability in much the same way as observedwith metoprolol. In fact this seems not to be thecase; a high-protein meal has been reportedto have no effect on verapamil bioavailability(Woodcock et al., 1986).

Antimicrobial drugs It has long been knownthat the bioavailability of the antifungal agentgriseofulvin, and the urinary antiseptic agentnitrofurantoin is increased by high fat contentmeals. In the case of griseofulvin, the maximumplasma concentration increases by about 80%,while AUC increases by about 30%. This hasbeen said to be due to either fat-induced, or bilesalt-induced increase in the rate of absorptionfrom the small bowel (Crounse, 1961; Bates etal., 1966). However more recently, Palma etal. (1986) have shown that the effect is due toenhancement of solubilisation of griseofulvin byfat, and that fat and bile salts have no directeffect on the rate of its absorption. Since thedrug has a relatively wide therapeutic index, the

interaction is usually not of great clinical signifi-cance, though it should be remembered thatgriseofulvin produces concentration dependentinduction of some liver enzymes. Nitrofurantoinis also poorly soluble in water, and incompletelyabsorbed following oral administration.

Coadministration with food increases thebioavailability of nitrofurantoin by up to 400%(Rosenberg & Bates, 1976). This effect is maxi-mal for those formulations of the drug with thepoorest dissolution characteristics, suggestingthat the effect is at least in part due to betterdissolution resulting from delayed gastric empty-ing (Rosenberg & Bates, 1976). In contrast tothese observations concerning nitrofurantoin,the bioavailability of the newer quinolone anti-biotics (e.g. ciprofloxacin) is not greatly per-turbed by food (Neuman, 1988). Finally on thesubject of antibacterial drugs, as mentionedabove, the bioavailability of erythromycin esto-late formulations, but not of the stearate, isincreased by food.Most of the drugs referred to so far are in

standard use in the United Kingdom, but men-tion must be made of some drugs rarely used inBritish practice. The clinical pharmacokineticsof antihelminthic drugs have recently been re-viewed by Edwards & Breckenridge (1988).One of these, mebendazole, when given to fast-ing healthy subjects, achieved plasma concen-trations below 18 nmol - 1; when the same dosewas given to the same subjects with fatty food,the peak plasma concentrations were 91, 112and 142 nmol 1- 1 and AUC was similarly in-creased (Munst et al., 1980). Flubendazole isa p-fluoro derivative of mebendazole. Whengiven with fatty food, like mebendazole itachieves higher plasma concentrations (Michielset al., 1982). The principal clinical importanceof these observations is that higher systemicconcentrations of these poorly absorbed drugscan be obtained by coadministration with fattyfood, and this is advantageous when treatingsystemic helminth infections (e.g. hydatid).Another drug used mainly in the tropics, andwhose bioavailability seems to be increased byfood, is the phenanthrenemethanol antimalarialdrug halofantrine. This compound is clinicallyeffective against multi drug resistant Plasmodiumfalciparum in many parts of the world. Unfor-tunately the absorption of halofantrine is in-complete after oral administration, and can beerratic with some of the formulations underassessment (Horton, 1988). Following a fattymeal, Milton et al. (1989) have shown thatAUC for both the parent drug and its equipotentdesbutyl metabolite increase from 3.9 ± 2.6 and8.8 ± 3.5 mg 1-1 h respectively, to 11.3 ± 3.5

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and 10.7 ± 3.2 mg l-1 h respectively. Theclinical relevance of this observation is not yetclear, but if the drug is to be used for 'presump-tive' self treatment by otherwise fit travellerstaking a standard European diet, the effect maybe important.

Antiepileptic drugs Phenytoin has unpleasant,and sometimes dangerous, concentration de-pendent adverse effects. The situation is com-plicated by the drug's saturatable hepatic meta-bolism, making phenytoin a potentially difficultdrug to use to optimum effect. Inter individualvariation in response to phenytoin can arisefrom its time of administration with relation tomeals, since food increases both the rate ofappearance of the drug in the plasma and itsoral bioavailability. The effect seems to be dueto an increase in the rate and extent of absorp-tion, and not to perturbation of first pass meta-bolism (Melander et al., 1979b).

Anticoagulants Melander & Wahlin (1978)have shown that the extent of absorption ofdicoumarol is significantly increased by food.However, this drug is not used frequently in theU.K. Food seems not to perturb the bioavail-ability of the more frequently used drugs warfarinand phenindione, although there is one reportsuggesting reduced effectiveness of these agentsin the presence of food (Welling, 1984).

Conclusions

(i) In both short and long-term drug treat-ment compliance is often difficult and inthe elderly can be impossible. Conse-quently, linking drug doses to regularevents such as meals makes sense, and hasbeen shown to improve compliance(Haynes et al., 1976). Drugs will oftenbe taken before the meal, on an emptystomach, and if even a short time elapsesbefore the food is taken, much of the drugwill usually have been cleared from thestomach and no interaction with the foodwill occur. Drugs taken at the same timeas food are more prone to interaction bythe mechanisms described above, but evenhere there are few clinically importantexamples.

(ii) If coadministration of a drug with fooddoes cause therapeutic failure, then thedrug concerned needs to be taken on anempty stomach. Fortunately such examplesare few and include; glibenclamide, glipizide,atenolol, captopril and several antibiotics,including isoniazid and rifampicin.

(iii) Because of the risk of concentration-de-pendent adverse effects, some drugs shouldbe taken at set times with relation to meals.These include: phenytoin, propafenone,labetalol, propranolol, and metoprolol.

(iv) Some drugs which are poorly absorbed afteroral administration but lack a parenteralformulation, can be made more systemicallyavailable by administration with food. Theseinclude: mebendazole, flubendazole, nitro-furantoin, griseofulvin and halofantrine.

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(Received 31 March 1989,accepted 11 August 1989)