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.