Influence of Food Intake on Presystemic Clearance of Drugs

Abstract

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. 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 (esterified) 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 enzymes 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 food 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.

Effect of a high protein meal on the bioavailability of verapamil.

“…Indeed, the mean peak plasma concentration (Cma) of verapamil if anything tended to be lower after food, 77 ng ml[,, in comparison with the fasting state, 118 ng ml-, P < 0.1 (Table 1). This is an unexpected observation since our standard meal contained 34 g protein, which in the study of Walle et al Melander & McLean (1983) have suggested that the food effect on bioavailability may only occur with drugs undergoing hydroxylation and conjugation since a standardised breakfast had no effect on the bioavailability of amitryptiline and prazosin where the presystemic metabolism involves dealkylation. The primary metabolic pathways of verapamil are N-dealkylation and O-demethylation (Eichelbaum et al, 1979) and thus our findings are consistent with this hypothesis.…”

The influence of food on the pharmacokinetics of ‘biphasic’ nifedipine at steady state in normal subjects.

“…Nifedipine undergoes first pass metabolism with a bioavailability in the region of 40-70% (Waller et al, 1984). Food has been shown to influence the pre-systemic clearance of some drugs such as propranolol and prasozin (Melander & McLean, 1983 that the extent of nifedipine absorption was influenced by food and it therefore seemed unlikely that such mechanisms were operating in the case of nifedipine.…”

Stable oral availability of sustained release propranolol when co‐ administered with hydralazine or food: evidence implicating substrate delivery rate as a determinant of presystemic drug interactions.

“…Superficially, observations related to food and hydralazine suggest that flow-mediated mechan- (McLean et al, 1978) regardless of the model which applied. Similarly, effects of shunt processes over similar time frames would tend to be obscured by delayed absorption of drug (Melander & McLean, 1983). The processes underlying the interaction remain unexplained even though long-term metabolic inhibition appears to be excluded.…”

“…The processes underlying the interaction remain unexplained even though long-term metabolic inhibition appears to be excluded. A variety of mechanisms are possible, including short-term inhibition of enzymes, short-term changes in flow, or redistribution of flow with non-homogenous distribution of enzymes (Melander & McLean, 1983).…”

“…Byrne et al that the reported interaction between hydralazine and food (Melander et al, 1977a) disappeared when the influence of food on a sustained-release formulation of hydralazine was studied (Liedholm et al, 1983). Because of the potential implications of this result (Melander & McLean, 1983) the propranolol-hydralazine and propranolol-food interactions were re-examined using sustained release propranolol (Inderal LA® ) as an alternative model substrate, given the difference in metabolism between hydralazine and propranolol (Melander & McLean, 1983).…”