Summary

Clinical Pharmacokinetics 8: 286-296 (1983) 0312-5963/83/0700-0286/$05.50/0 © ADIS Press Australasia Pty Ltd. All rights reserved.

Influence of Food Intake on Presystemic Clearance of Drugs

Arne Melander and Allan McLean Department of Clinical Pharmacology, University of Lund, The Health Sciences Centre, Dalby, and Clinical Research Unit and Monash University Department of Medicine, Alfred Hospital, Melbourne

Many drugs have a low degree of oral bioavailability even though their gastrointestinal absorption is complete. This is because they undergo extensive presystemic metabolic trans­formation during the first passage of the drug through the gastrointestinal mucosa and the liver. In addition to effects on the absorption of some drugs, food intake has been found to influence the bioavgilability of drugs with extensive presystemic metabolic clearance.

Extensive presystemic clearance occurs commonly with compounds that are lipophilic bases. e.g. propranolol and amitriptyline, but rarely if ever with lipophilic acids, e.g. salicylic acid and penicillin, except for esters of such acids, e.g. acetylsalicylic acid (aspirin) and pivampicillin. While presystemic clearance of(esterijied) acidic drugs is unaffected by food, concurrent food intake markedly reduces presystemic clearance, and thus enhances bio­availability, of several lipophilic bases. Among these are propranolol, metoprolol, labetalol, dixyrazine and hydralazine, which are presystemically metabolised by hydroxylation, glu­curonidation and acetylation enzyme systems. In contrast, the bioavailability of lipophilic bases which undergo presystemic dealkylation (amitriptyline, codeine, dextropropoxyphene, prazosin, zimelidine) is unaffected by concurrent food intake. Food intake reduces presys­temic clearance of hydralazine and propranolol when these drugs are administered in con­ventional rapid-release tablets but not when they are given in slow-release formulations. Likewise, coadministration of hydralazine reduces presystemic clearance of rapid-release but not slow-release propranolol. These and other observations favour the view that food may reduce presystemic clearance of (certain) lipophilic basic drugs via transient, complex effects on splanchnic-hepatic blood flow and/or shunt processes, and that the extent of this effect is influenced by the rate of drug delivery to the liver. In addition, these findings refute the notion that the reduced presystemic clearance results from (long-lasting) hepatic enzyme inhibition by some nutrient. On the other hand, repeated intake of specific nutrients (protein) and faod contaminants (benzpyrene) can enhance presystemic drug clearance by enzyme induction. Thus, food may exert a dual effect on presystemic drug clearance. A complete evaluation of the influence of food on presystemic drug clearance necessitates bioavailability studies carried out following both single and repeated meals, including different kinds of food prepared by various cooking methods.

The influence of food on the presystemic clearance of drugs is most likely to be clinically relevant with drugs having narrow therapeutic margins and/or steep dose-response curves.

Food Intake and Presystemic Clearance 287

Its importance may be minimised by stipulating that drugs always be taken in the same relation to meals. Alternatively. the problem can be circumvented by employing formulations that minimise the food influence. or by the use of drugs that have little or no presystemic clearance.

Many drugs have a low degree of oral bioavail­ability even though their gastrointestinal absorp­tion is complete. This is because they undergo extensive presystemic metabolic transformation during the first passage of the drug through the gas­trointestinal mucosa and the liver. In addition to effects on the absorption of some drugs, food in­take has been found to influence the bioavailability of drugs with extensive presystemic metabolic clearance. This review discusses the different clinical and experimental findings, pharmacokin­etic models and potential mechanisms of food-drug interactions, together with the clinical implications of these interactions for routine drug use.

1. Food and Oral Drug Use: General Considerations

Misconceptions regarding the nature of the pro­cess of drug absorption and the influence of food

"on drug absorption led to endorsements by medi­cal authorities of the concept of separating drug intake from food intake (Koch-Weser, 1974; Well­ing, 1977). However,the recognition that food only rarely compromises oral availability of drugs (Me­lander, 1978), together with the potential role of the food-drug conjunction in enhancing compli­ance (McLean and Melander, 1983), indicates that the previous recommendations may need to be re­versed; i.e. food and drugs should be co-adminis­tered whenever possible.

Further interest in the mechanisms offood-drug interactions arises from an awareness that these processes may be applicable to drug-drug interac­tions, to physiological phenomena such as regula­tion of the delivery of intestinal and pancreatic hormones and high clearance food substrates (e.g. galactose) to the systemic circulation, and to reg-

ulation of the entry of high clearance xenobiotic materials (toxins, carcinogens, teratogens) from the environment via the gut (Gibby and Hales, 1983; McLean et aI., 1981).

2. Food and Drug Bioavailability

Drugs are usually administered orally, on the assumption that they will be absorbed in the gas­trointestinal tract, traverse the liver and lungs, reach the systemic circulation, and thence be distributed to their sites of action in the tissues. For many drugs, however, a considerable fraction of the in­gested dose never reaches systemic circulation; in other words, the bioavailability of the drug is in­complete. In some instances there may be great in­terindividual variation in bioavailability and hence in steady-state concentration and effect. In addi­tion, the variation within individuals may be con­siderable.

In principle, drug bioavailability is governed by the processes of absorption and presystemic clear­ance, and these are influenced by both genetic and environmental factors including the intake offood. The usual tests of oral availability involve only measurement of the fraction of unchanged drug reaching the systemic circulation after oral intake as compared with that following intravenous in­jection in the same individual (absolute bioavail­ability). Valuable data on relative bioavailability can be obtained by comparing AVe (area under the plasma concentration-time curve) values, or urinary excretion values, following intake of dif­ferent pharmaceutical preparations of the same drug. Assessments of the influence of food intake on drug bioavailability are usually carried out by comparison of AVe values, or urinary excretion values, following intake of a drug both under fast-

Food Intake and Presystemic Clearance

ing and non-fasting conditions. While extraction by the lungs may constitute an important element of presystemic clearance for some drugs, the scope of this review excludes consideration of evidence relating to presystemic clearance by the lung.

2.1 Influence of Food Intake on Absorption of Drugs

The ingestion of food initiates a complex series of events, which may affect drug absorption in dif­ferent ways. Food intake can influence tablet dis­integration, drug dissolution, the rate of gastric emptying, gastrointestinal secretion, and active transport of drugs (Melander, 1978, 1981). Such mechanisms are probably responsible for the food­induced enhancement of the bioavailability of di­coumarol (Melander and W;1hlin, 1978), phenytoin (Johansson et aI., 1983; Melander et aI., I 979a), hydrochlorothiazide (Beermann and Groschinsky­Grind, 1978) and nitrofurantoin (Bates et al., 1974), as well as for the food-induced reduction of the bio­availability of isoniazid (Melander et aI., 1976), rif­ampicin (Acocella, 1978), atenolol (Melander et aI., 1979b) and captopril (Williams and Sugerman, 1982).

Moreover, specific nutrients may influence drug absorption: phenytoin absorption is enhanced by carbohydrates but impaired by protein (Johansson et aI., 1983), while that of griseofulvin is enhanced by fat (Crounse, 1963). The influence of food on drug absorption has been reviewed previously in the journal (Melander, 1978); hence the present re­view is restricted to the influence of food on pre­systemic clearance of drugs.

2.2 Influence of Food on Presystemic Clearance of Drugs

Several drugs have complete gastrointestinal ab­sorption, but incomplete bioavailability. This is because they undergo extensive presystemic meta­bolic transformation during their first passage through the gastrointestinal mucosa and the liver (Harris and Riegelman, 1969). As the gene-de­pendent drug-metabolising capacity differs exten-

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sively between individuals, there is a large inter­individual variation in bioavailability of drugs that undergo such presystemic clearance, e.g. propran­olol (Melander et aI., 1977b), hydralazine (Talseth, 1977), phenacetin (Conney et aI., 1976) and aspirin (Brantmark et aI., 1982). In addition, the degree of presystemic clearance can be markedly influenced by environmental factors including food intake, specific nutrients, food contaminants, smoking, al­cohol and (other) drugs.

Presystemic metabolism may occur in the gas­trointestinal mucosa, presystemic blood, liver and lungs. It must be borne in mind, however, that bio­availability data obtained by comparisons of drug concentration profiles following intravenous and oral administration reflect the sum of metabolic transformations in the gastrointestinal mucosa, splanchnic-hepatic blood and liver, but exclude pulmonary effects.

3. Experimental and Clinical Findings

The influence of food on presystemic drug clearance is complex, since single and repeated food intake may have opposite effects, as can different kinds of food or differently prepared food. In ad­dition, wholly appropriate data can be obtained only if the drug is given both orally and intraven­ously; otherwise, food effects on presystemic drug metabolism and on drug distribution cannot be safely distinguished (Daneshmend and Roberts, 1982).

With these reservations stated, the following sections review the currently available information on the influence of food intake on presystemic drug clearance. Most investigations have been limited to single meal effects on single dose bioavailability following concomitant oral intake.

3.1 Influence of Concomitant Food Intake on Presystemic Clearance of Different Drugs

3.1.1 p-Adrenoceptor Antagonists Current intake of a standardised breakfast of

1840kJ (440 kcal), including 20g (20%) protein, SOg

Food Intake and Presystemic Clearance

(45%) carbohydrate and 17g (35%) fat, enhanced the bioavailability of propranolol by about 50% and that of metoprolol by about 40% (Melander et aI., 1977b). As the absorption of propranolol and me­toprolol is complete in the fasting state, the food­induced bioavailability increase could hardly be due to improved absorption; rather, it is due to reduced presystemic metabolism (Melander et aI., I 977b).

The food-propranolol interaction was con­firmed by Mclean and co-workers (Mclean et aI., 1981). Absorption data derived from urinary re­covery of tracer doses of 1-14C-propranolol label and measurements of systemic clearance empha­sised that the enhanced bioavailability reflected al­teration in presystemic clearance (Mclean et aI., 1981). Walle and co-workers suggested that the food-induced increase in propranolol bioavailabil­ity is proportional to the amount of protein in the meal (Walle et aI., 1981), but Mclean and co­workers reported similar increments after a pre­dominantly carbohydrate stimulus and a high pro­tein-lipid meal (Mclean et aI., 1981). Recent ob­servations indicate that food does not reduce the presystemic clearance of propranolol when the drug is given in a slow-release formulation (Byrne et at, 1983). This is analogous to findings with hydral­azine (Liedholm et aI., 1983) and is of considerable mechanistic interest (see section 5).

Like propranolol and metoprolol, labetalol, the combined Q!- and {j-adrenoceptor antagonist is sub­ject to considerable presystemic clearance, and also exhibits a food-induced increase in bioavailability (Daneshmend and Roberts, 1982). As there was little or no influence of food on intravenous la­betalol kinetics, it could be ascertained that the food effect is exerted on the presystemic clearance rather than on the distribution of the drug (Daneshmend and Roberts, 1982).

In contrast to propranolol, metoprolol and la­betalol, pindolol, although subject to extensive sys­temic metabolism, escapes presystemic clearance. In accordance with this, its bioavailability was found to be unaffected by concurrent food intake (Kiger et aI., 1976). In addition, the bioavaiiabiIity of the hydrophilic ,8-adrenoceptor antagonists at­enolol and sotalol, both of which are absorbed and

289

excreted without preceding metabolic transforma­tion, is reduced instead of enhanced by concurrent food intake (Kahela et aI., 1979; Melander et aI., 1979b), probably due to impaired absorption (Me­lander et a1., 1979b).

3.1.2 a-Adrenoceptor Antagonists Although subject to considerable presystemic

clearance, prazosin does not display any change in bioavailability when given together with food (Brogden et aI., 1977; Stanaszek et aI., 1983).

3.1.3 Hydralazine In contrast to that ofprazosin (see section 3.1.2),

the bioavailability of the vasodilator hydralazine is strongly enhanced by concomitant intake of the standardised breakfast described in section 3.1.1 (Melander et aI., 1977a). This is most pronounced for 'apparent' hydralazine, i.e. hydrazones formed between hydralazine and pyruvic acid and other keto acids, but also occurs with 'real' hydralazine (Liedholm et aI., 1983). As hydralazine is com­pletely absorbed, the bioavailability increase most probably reflects reduced presystemic clearance (Liedholm et aI., 1983).

In analogy with findings concerning the food­propranolol interaction (section 3.1.1), a food-in­duced enhancement of hydralazine bioavailability did not occur when the drug was given as a slow­release preparation (Liedholm et aI., 1983). This has considerable mechanistic interest, as discussed below.

3.1.4 Antidepressants Recent studies indicate that concomitant intake

of the standardised breakfast described above (sec­tion 3.1.1) has little or no influence on the bio­availability of amitriptyline (Liden et aI., submit­ted for publication). Like amitriptyline, the new antidepressant zimelidine displayed no change in its bioavailability following concomitant standar­dised breakfast intake (Wahlen et aI., 1983).

The absence of a food effect on these 2 anti­depressants is of interest as their presystemic me­tabolism, like that of prazosin, involves dealkyla­tion (see further below).

Food Intake and Presystemic Clearance

3.1.5 Narcotic Analgesics Although most narcotic analgesics exhibit pro­

nounced presystemic clearance and have narrow therapeutic margins, few investigations have ex­amined the possible influence of food intake. Con­comitant intake of the standardised breakfast (sec­tion 3.1.1) did not affect the presystemic clearance of dextropropoxyphene from a combination tablet also containing aspirin, phenazone and caffeine (Melander et aI., 1 977c). When given as dextro­propoxyphene hydrochloride alone, the drug dis­played no change or a slight increase in bioavail­ability when taken with food (Welling et a!., 1976).

Likewise, codeine given in a novel combination with paracetamol showed no change in presystemic clearance when the combination was given to­gether with the standardised breakfast (Elofsson et aI., in preparation).

3.1.6 Anti-inflammatory Analgesics With the exception of aspirin and phenacetin,

most anti-inflammatory analgesics display negli­gible presystemic clearance. Concomitant intake of the standardised breakfast (section 3.1.1) reduced the peak concentration, but seemingly not the bio­availability, of unchanged aspirin, implying that its rate of absorption, but not its presystemic clear­ance, is altered (Melander et aI., submitted for pub­lication).

There is no available information on the influ­ence of concomitant food intake on the presys­temic clearance of phenacetin, but there is evi­dence (Conney et aI., 1976) that repeated intake of charcoal-broiled beef enhances presystemic clear­ance of this drug (see also section 3.3).

3.1.7 Antipsycholics Several, if not all, antipsychotic drugs undergo

presystemic clearance, but little is known about the influence of concomitant food intake. Dixyrazine has recently been found to undergo extensive pre­systemic clearance, apparently by hydroxylation. This is markedly reduced if the drug is taken with food; the relative bioavailability is increased by al­most 100% (Melander et aI., in preparation). On the other hand, the standardised breakfast (section

290

3.1.1) did not seem to affect presystemic clearance of mel perone (Larsson et a!., in preparation), an antipsychotic agent which apparently undergoes presystemic clearance by dealkylation (Borgstrom et aI., 1982).

3.1.8 Esters of Drug Acids Esterified drug acids such as acetylsalicylic acid

(aspirin), carbimazole (Melander et aI., 1980), and pivampicillin are subject to extensive presystemic clearance by esterases present in the gut, liver and blood. However, this process is apparently not af­fected by food intake; the bioavailability of am­picillin from pivampicillin is not changed (RohoIt et aI., 1974) and, although the peak concentration of aspirin is reduced, its bioavailability appears to be unaltered (see also section 3.1.6).

3.2 Influence of Repeated Food Intake on Presystemic Clearance of Drugs

Repeated intake of protein-rich meals can en­hance systemic clearance of drugs such as theo­phylline and antipyrine (Anderson et aI., 1979). This is probably due to hepatic enzyme induction, and such a change should also be able to affect pre­systemic drug clearance, although direct evidence is lacking. It must be re-emphasised that this phen­omenon signifies that food may have a dual effect on presystemic drug clearance (see below).

3.3 Influence of Repeated Exposure to Food Contaminants on Presystemic Drug Clearance As previously described (section 3.1.6), repeated

intake of charcoal-broiled beef enhances the pre­systemic clearance of phenacetin (Conney et aI., 1976), and it has also been shown to enhance sys­temic clearance of antipyrine and theophylline (Kappas et a!., 1978). This effect is probably due to contamination of the food with benzpyrene, causing enzyme induction in the gut and/or the liver. A similar effect could occur with all drugs that are metabolised by the same enzyme sys­tem(s), providing a further mechanism for the dual effect of food on presystemic drug clearance.

Food Intake and Presystemic Clearance

4. Mechanisms Regulating Hepatic Metabolism and Hepatic Extraction

The general relationship governing hepatic (drug) clearance (CLH ) is obtained using Fick's principle and is given by:

CLH = Q X E

where Q represents the hepatic perfusion rate and E represents the extraction fraction across the liver, i.e.:

Ci - Co

Cj E=

C j and Co signifying substrate concentrations in total inflow and hepatic venous outflow, respec­tively. Changes in clearance can only result from an alteration in Q or E. The unresolved questions concerning food effects focus on the mechanisms mediating alterations in E with specific attention to the interaction between Q and E. As detailed below, pharmacologists have tended to interpret food-drug and drug-drug interactions of the type discussed above in terms of sinusoidal mechanisms only, with sinusoidal function described by 2 simple models. However, the functional and structural diversity of the liver together with the complexities of the he­patosplanchnic circulation require more compre­hensive analyses.

4.1 Venous Equilibrium and CapiJIary Extraction Models of Sinusoidal Activity

There are highly divergent views concerning the factors determining E and the influence of Q on E in the hepatic sinusoids. A commonly accepted model is the venous equilibrium model (A) pro­posed by Rowland et a!. (1973). In this model, the hepatic sinusoids are assumed to be anatomically and functionally homogeneous and that all cells ex­perience a concentration of free substrate which is in equilibrium with the venous outflow concentra­tion (Co). An alternative model, the capillary ex­traction model (B) proposed by Winkler et al. (1974), similarly assumes that the sinusoids are ho­mogeneous, but differs in proposing that cells ar-

291

ranged sequentially along the sinusoid will expe­rience declining concentrations of substrate.

As discussed by Pang and Rowland (1977), these contrasting assumptions lead not only to many quantitative differences in the behaviour of these models but also to diametrically opposed predic­tions as to the influence of alterations in hepatic blood flow both on the oral (portal) single dose area under the concentration-time curve in peripheral plasma (AU Co) and on the steady-state drug con­centration (Csso) during constant rate dosage deliv­ery by this route.

In the venous equilibrium model (A), AUCo and C"o are given by the following equation"s:

Dose A UCo = -,:---==-­

fB • CLI

Dose/t

fB • CLI

where CLI represents intrinsic (maximum) hepatic clearance which is independent of flow and free fraction (fB), and t represents the dosing interval. This model concedes that hepatic extraction is sen­sitive to changes in hepatic blood flow, decreasing as the flow increases. Pang and Rowland (1977) argue that the predicted flow independence of AUCo and Csso with this model is explained by the availability F and the clearance CL varying in di­rect proportion to flow, thus making the ratio F/ CL flow independent. So any change in oral bio­availability of high clearance drugs must be a re­flection of altered enzyme activity within the liver.

The corresponding relationships for the capil­lary extraction model (B) are:

Dose (e- f" CLdQ) AUCo = -----­

Q (1 - e-f" CL,Q)

(Dose/t) (e- f" CLI/Q) Csso = -------

Q (1 - e- f" CL"Q)

Model B dictates an exponential dependence of hepatic extraction on blood flow and thus the AUCo and Csso predicted by this model are vastly differ­ent to those predicted by model A, especially for highly extracted drugs. Indeed, model B predicts

Food Intake and Presystemic Clearance

sensitivity of oral bioavailability to hepatic blood flow. With this model, changes in oral bioavaila­bility of high clearance drugs evoked by concurrent food intake could be caused by both altered hepatic blood flow and changes in enzyme activity.

4.2 Alternative Sinusoidal Models

It has been realised that the above mentioned models ignore the structural and functional diver­sity of the liver, as well as that of the splanchnic­hepatic circulations. Recent progress in producing more realistic models of sinusoidal activity has been reported by Bass and co-workers (Bass et al., 1976, 1978; Bracken and Bass, 1979), who incorporated capacity-limited enzyme kinetics and heterogene­ity of the enzyme system(s) and sinusoidal flow paths into their models. Varying degrees of flow dependence can be assigned to their 'distributed' model according to the degree of variation allowed in the ratio of enzyme capacity (V max) to flow (f) in individual sinusoids (Bass and Robinson, 1979). Further refinement of these models may come with consideration of zonal disribution of enzymes (Rappaport and Schneiderman, 1976) and the pos­sibility of flow constraints on metabolism by in­direct means, e.g. regulation of oxygen delivery.

4.3 Extrasinusoidal Mechanisms

4.3.1 Phasic Flow In addition to the various sinusoidal aspects,

factors beyond the sinusoids need to be considered as providing mechanisms for alteration in drug handling by the liver, in particular phasic vascular phenomena. Phasic (short term) responses of splanchnic-hepatic blood flow to feeding have been described, and their capacity to alter drug bio­availability has been recognised (McLean et al., 1978). Specifically, it has been demonstrated that a transient increase in splanchnic-hepatic blood flow - as modelled on recorded food-drug interactions (Melander et al., 1977b) - could enhance the oral bioavailability of such drugs even if a flow-inde­pendent model of the liver itself were assumed (Mclean et al., 1978). In support of this model,

292

ingestion of the vasodilator hydralazine, which is known to enhance splanchnic-hepatic blood flow, has been found to increase the bioavailability of co-administered propranolol (Mclean et al., 1980), and administration of a slow-release formulation of propranolol ablated both the interaction asso­ciated with hydralazine and with food (Byrne et al., 1983). Furthermore, co-administration of the va­sodilator glyceryl trinitrate and the high clearance drug dihydroergotamine gave a similar increase in dihydroergotamine bioavailability (Bobik et al., 1981). Moreover, similar phasic vascular responses have been described in anaesthetised dogs main­tained with flow probes on hepatic and mesenteric arteries following introduction of hydralazine into the lumen of the mid-gut (Heinzow and Mclean, 1982).

4.3.2 Phasic Vascular Shunts Phasic shunt reactions must also be considered.

These shunts could exist within the liver itself (Grayson and Mendel, 1965) or at other sites of anatomical continuity between the systemic and splanchnic circulations. The influence of hepatic shunting on the fractional availability (F) of a drug has been described as follows (McLean et al., 1979):

F = I _ E = Qs + QL (QL' QL + Qs QL + Qs QL + Cll)

where Qs is shunt flow, QL hepatic perfusion and Cl i intrinsic hepatic clearance. Phasic (short term) shunts confined to presystemic drug hand­ling would exert a similar influence on AUCo as the phasic changes in hepatic perfusion mentioned above (Mclean et al., 1978).

5. Mechanisms 0/ Food Influence on Hepatic Clearance and Hepatic Extraction 5.1 Direct Influence of Food on Drug­Metabolising Enzymes

Mediation of food effects by direct inhibition of metabolism is a postulate consistent with the ven­ous equilibrium model (see section 4.1). Because drugs subject predominantly to dealkylation (ami-

Food Intake and Presystemic Clearance

triptyline, codeine, dextropropoxyphene, prazosin, zimelidine; see above) are not affected, whereas drugs exposed to hydroxylation, giucuronidation and acetylation are affected (propranolol, meto­prolol, labetalol, dixyrazine, hydralazine; see above), it would be attractive to propose a gener­alisation based on differential effects on these metabolic pathways. However, there is reason to discount this concept. Walle et al. (1981) showed that the plasma levels of propranolol metabolites, including conjugates, were not reduced by food. Moreover, it has recently been shown that a food­induced reduction of the presystemic clearance of hydralazine and of propranolol does not occur when these agents are administered in slow-release for­mulations (Byrne et ai., 1983; Liedholm et ai., 1983). As competitive inhibition would be more effective at lower and more stable substrate con­centrations, but effects of flow-mediated changes or shunt processes would be diminished, these findings favour the view that the food effect involves flow or shunt mechanisms, and that the extent of the effect is influenced by the rate of drug delivery to the liver.

To date, the only direct effects of food on drug metabolism have been inductive effects (Conney et ai., 1976) [see section 3.3].

5.2 Effects Exerted via Altered Sinusoidal Perfusion

Food produces well documented effects on splanchnic blood flow which have been previously reviewed in the context of drug bioavailability (McLean et ai., 1978). The absence of effects of food on high clearance drugs primarily subject to dealkylation is not compatible with a flow effect on a simple system such as the flow-sensitive cap­illary extraction model (see section 4.1), even if phasic vascular phenomena were invoked.

5.3 Flow Effects on a Distributed Sinusoidal Model

The distributed model of Bass and co-workers (see section 4.2) would allow flow sensitivity and

293

differential metabolic effects according to the ana­tomical distribution and capacity limitation of dif­ferent enzyme systems. Transient increases in splanchnic-hepatic blood flow with transient in­creases in substrate loads would provide a partic­ular example of mechanisms which could apply.

Insight into mechanisms should come from ex­periments in which representative metabolic sub­strates are used, and in which flow and extraction are measured directly with controlled perturba­tions of relevant parameters under 'in vivo' con­ditions (see Heinzow and McLean, 1982). Insight will also emerge from studies involving controlled substrate delivery, as has been described above for hydralazine (Liedholm et ai., 1983) and propran­olol (Byrne et a!., 1983). It should be noted partic­ularly that the combination of high portal drug concentrations during the absorptive phase and potential redistribution of flow as part of the feed­ing response are not amenable to duplication by experiments involving systemic drug dosing.

6. Clinical Implications of Food Effects on Presystemic Hepatic Clearance

Both an increase in peak plasma concentration and an increase in bioavailability present mech­anisms whereby food could alter the clinical re­sponses to a drug. An altered bioavailability in conjunction with stable clearance during the ma­jority of the interdose intervals should result in higher steady-state plasma concentrations of drug. One of the several deficiencies in this area of study remains the lack of studies which have addressed themselves to steady-state drug dosing. At present, the problem cannot be assessed at the clinical level.

Similarly, altered peak concentrations hold the potential for altered clinical effects when the con­centration of drug is closely tied to effect. If the perturbations of peak concentration described in the single dose situation apply to steady-state dos­ing, then low clearance agents might be preferred.

A food-drug interaction is most likely to be clinically relevant if the drug has a narrow thera­peutic margin and/or a steep dose-response curve.

Food Intake and Presystemic Clearance

Its importance may be minimised by stipulating that a high clearance drug always be taken in the same relation to meals, preferably together with the meal, and/or by giving the drug in a formulation (slow-release) minimising the influence offood. Al­ternatively, the problem can be circumvented by using drugs with stable absorption and little or no presystemic clearance,

7. Conclusions

In general, drugs should be taken together with food as a compliance aid and as a means of re­ducing local gastrointestinal effects. Although in­teractions between food and a number of high clearance lipophilic bases have been described, agents subject primarily to dealkylation reactions do not appear to be influenced in the same way as drugs which undergo primary metabolism by other pathways.

The mechanisms of food-drug interactions are not known; however, simple explanations in terms of individual processes such as enzyme inhibition or alteration in blood flow can be ruled out. Com­plexities of hepatic structure and enzyme distri­bution together with integrated responses ofthe he­patosplanchnic circulation need to be invoked to explain existing observations.

Irrespective of the mechanisms involved, the described interactions lead to practical therapeutic recommendations. High clearance drugs should be ingested in fixed relatIonship to meals and/or ad­ministered in a formulation (slow-release) min­imising the influence of food; alternatively, drugs with stable absorption and little or no presystemic clearance should be prescribed instead.

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Byrne, A.1.; McNeil, J.1.; Harrison, P.M.; Louis, W.; Tonkin, A.M. and Mclean, A.J.: Stable oral availability in man of sustained release propranolol (Inderai LA ®) coadministered with hy· draliazine and food - Evidence implicating substrate delivery rate as a determinant of presystemic drug interactions. British Journal of Clinical Pharmacology (In press, 1983).

Conney, A.H.; Pantuck, E.1.; Hsiao, K .• C.; Garland, W.A.; An· derson, K.E.; Alvares, A.P. and Kappas, A.: Enhanced phen. acetin metabolism in human subjects fed charcoal·broiled beef. Clinical Pharmacology and Therapeutics 20: 633-642 (1976).

Crounse, R.G.: Effective use of griseofulvin. Archives of Der­matology 87: 176-180 (1963).

Daneshmend, T.K. and Roberts, C.1 .c.: The influence of food on the oral and intravenous pharmacokinetics ofa high clearance drug: A study with labetalol. British Journal of Clinical Pharmacology 14: 73·78 (l982).

Gibby, O.M. and Hales, C.N.: Oral glucose decreases hepatic ex­traction of insulin. British Medical Journal 286: 921·923 (1983).

Grayson, J. and Mendel, D.: Anatomy of the hepatic circulation; in Barcroft et al. (Eds) Physiology of the Splanchnic Circu· lation; Monographs of the Physiological Society, pp.56.62 (Edward Arnold Ltd, London 1965).

Harris, P.A. and Riegelman, S.: Influence of the route of admin­istration on the area under the plasma concentration-time curve. Journal of Pharmaceutical Sciences 58: 71-75 (1969).

Heinzow, B. and Mclean, AJ.: Apparent flow dependent hepatic

Food Intake and Presystemic Clearance

clearance of propranolol incompatible with the venous equi­librium model of sinusoidal extraction. Clinical Pharmacol­ogy and Therapeutics 31: 234 (1982).

Johansson, b.: Wahlin-Boll, E.; Lindberg, T. and Melander, A.: Opposite effects of carbohydrate and protein on phenytoin. absorption in man. Drug Nutrient Interactions (In press, 1983).

Kahela, P.; Anttila, M.; Tikkanen, R. and Sundquist, H.: Effect of food, food constituents and fluid volume on the bioavail­ability of sotalol. ACla Pharmacologica et Toxicologica 44: 7-II (1979).

Kappas, A.: Alvares, A.P.; Anderson, K.E.: Pantuck, E.J.: Pan­tuck, CB.: Chang, Rand Conney, A.H.: Effect of charcoal­broiled beef on antipyrine and theophylline metabolism. Clinical Pharmacology and Therapeutics 23: 445-450 (1978).

Kiger, J.L.: Lavene, D.: Guillaume, M.F.: Guerret, M. and Longchampt, J.: The effect of food and c10pamide on the ab­sorption of pindolol in man. International Journal of Clinical Pharmacology 13: 228-232 (1976).

Koch-Weser, J.: Bioavailability of drugs. New England Journal of Medicine 291: 233-237 and 503-506 (1974).

Liedholm, H.: Wahlin-Boll, E.: Hanson, A. and Melander, A.: Influence of food on the bioavailability of 'real' and 'appar­ent' hydralazine from conventional and slow-release prepar­ations. Drug Nutrient Interactions I: 293-302 (1983).

Mclean, A.J.: du Souich, P. and Gibaldi, M.: Non-invasive phar­macokinetic method for the estimation of total hepatic blood flow and the degree of shunting of blood in patients with chronic liver disease - a hypothesis. Clinical Pharmacology and Therapeutics 25: 161-166 (1979).

McLean, AJ.: Isbister, C: Bobik, A. and Dudley, FJ.: Reduction of first-pass hepatic clearance of propranolol by ingestion of food. Clinical Pharmacology and Therapeutics 30: 31-34 (1981).

McLean, AJ.: McNamara, P.: du Souich, P.; Gibaldi, M. and Lalka, D.: Food, splanchnic blood flow and bioavailability of drugs subject to first-pass metabolism. Clinical Pharmacology and Therapeutics 24: 5-10 (1978).

Mclean, AJ. and Melander, A.: The influence of food on oral drug usage. Current Therapeutics 24, No 8 (Aug. 1983).

Mclean, AJ.: Skews, H.; Bobik, A. and Dudley, FJ.: Interaction between oral propranolol and hydralazine - mechanism and therapeutic implications. Clinical Pharmacology and Thera­peutics 27: 726-732 (1980).

Melander, A.: Influence of food on the bioavailability of drugs. Clinical Pharmacokinetics 3: 337-351 (1978).

Melander, A.: Food intake and drug bioavailability: in Progress in Clinical and Biological Research, Vol. 77: Nutrition in Health and Disease and International Development: Sym­posia from the XII International Congress of Nutrition, San Diego, pp.747-756 (Alan Liss Inc, New York 1981).

Melander, A.: Berlin-Wahlen, A.; Bodin, N.-O.; Danielson, K.; Gustafsson, B.; Lindgren, S. and Westerlund, D.: Bioavaila­bility of d-propoxyphene, acetylsalicylic acid, and phenazone in a combination tablet (Doleron®): Interindividual variation and influence of food intake. Acta Medica Scandinavica 202:

295

119-124 (1977c). Melander. A.; Brante, G:, Johansson, b.; Lindberg, T. and W~hlin­

Boll. E.: Influence of food on the absorption of phenytoin in man. European Journal of Clinical Pharmacology IS: 269-274 (I'I79a).

Melander. A.: Danielson, K.: Hanson, A.; Jansson. L.; Rerup, C; Schersten, 8.: Thulin, T. and WAhlin, E.: Reduction of ison­iazid bioavailability in normal men by concomitant intake of food. Acta Medica Scandinavica 200: 93-97 (1976).

Melander. A.: Danielson, K.: Hanson. A.: Rudell, 8.: Schersten, 8.: Thulin. T. and W~hlin, E.: Enhancement of hydralazine bioavailability by food. Clinical Pharmacology and Thera­peutics 22: 104-107 (l977a).

Melander, A.: Danielson, K.; Schersten, 8. and W~hlin, E.: En­hancement of the bioavailability of propranolol and meto­prolol by food. Clinical Pharmacology and Therapeutics 22: 108-112 (l977b).

Melander, A.: Hallengren. B.: Rosendal-Helgesen, S.: Sjoberg, A.­K. and WAhlin-Boll. E.: Comparative in vitro effects and in vi vo kinetics of antithyroid drugs. European Journal of Clinical Pharmacology 17: 295-299 (1980).

Melander. A.: Stenberg. P.: Liedholm. H.: Schers({m. 8. and W~hlin-Boll. E.: Food-induced reduction in bioavailability of atenolol. European Journal of Clinical Pharmacology 16: 327-330 (1979b).

Melander. A. and W~hlin, E.: Enhancement of dicoumarol bio­availability by concomitant food intake. European Journal of Clinical Pharmacology 14: 441-444 (1978).

Pang. K.S. and Rowland, M.: Hepatic clearance of drugs. I. The­oretical considerations of a 'well-stirred' and a 'parallel tube' model. Influence of hepatic blood flow. plasma and blood cell binding. and the hepatocellular enzyme activity on hepatic drug clearance. Journal of Pharmacokinetics and Biophar­maceutics 5: 625-653 (1977).

Rappaport. A.M. and Schneiderman, J.H.: The function of the hepatic artery. Reviews in Physiology, Biochemistry and Pharmacology 76: 129-175 (l976).

Roholt. K.: Nielsen. 8. and Kristensen, E.: Clinical pharmacology ofpivampicillin. Antimicrobial Agents and Chemotherapy 6: 563-571 (1974).

Rowland. M.: Benet, L.Z. and Graham, G.G.: Clearance concepts in pharmacokinetics. Journal of Pharmacokinetics and Bio­pharmaceutics I: 123-126 {I 973).

Stanaszek, W.F.: Kellerman. D.; Brogden, R.N. and Romankiew­icz. J.A.: Prazosin update. A review of its pharmacological properties and therapeutic use in hypertension and congestive heart failure. Drugs 25: 339-384 (1983).

Talseth, T.: Clinical pharmacokinetics of hydralazine. Clinical Pharmacokinetics 2: 317-329 {I 977).

Wahlen. A.: Westerlund. D.: WlIhlin-Boll, E. and Melander. A.: Influence of food intake on the bioavailability of zimelidine and its active metabolite. norzimelidine. (In press. 1983).

Walle, T.: Fagan, T.C; Walle, K.; Oexmann, M.-J.; Conradi, E.C and Gaffney, T.E.: Food-induced increase in propranolol bio­availability - relationship to protein and effects on metabo-

Food Intake and Presystemic Clearance

lites. Clinical Pharmacology and Therapeutics 30: 790-795 (1981).

Welling, P.G.: How food and fluid affect drug absorption. Post­graduate Medicine 62: 73-82 (1977).

Welling, P.G.: Lyons, B.S.: Tse, M.S. and Craig, W.A.: Propoxy­phene and norpropoxyphene: Influence of diet and fluid on plasma levels. Clinical Pharmacology and Therapeutics 19: 559-565 (1976).

Williams, G.M. and Sugerman, A.A.: The effect of a meal. at various times relative to drug administration, on the bio­availability of captopril. Journal of Clinical Pharmacology (ACCP Meeting, Abstract 18A, (982).

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Winkler, K.: Bass, L.: Keiding, S. and Tygstrup, N.: The effect of hepatic perfusion on assessment of kinetic constants; in Lundquist and Tygstrup (Eds) Alfred Benson Symposium VI: Regulation of Hepatic Metabolism, pp.797-807 (Munksgaard. Copenhagen 1974).

Authors' address: Dr Arne Melander, Department of Clinical Pharmacology, University of Lund, The Health Sciences Centre, S-240 10 Dalby (Sweden).