Physiological Pharmaceutics

134 Physiological Pharmaceuticsantiarrhythmic agent, disopyramide 78 . It was postulated that this was due to the bidisomidebeing well absorbed in the upper but not lower small intestine.Certain components of food, notably fibre, have a particularly important effect ondrug absorption. Fibre is known to inhibit the absorption of digoxin and entrap steroids.It is well accepted that foods such as milk products, which have a high content of polyvalentmetals such as calcium, magnesium, iron, aluminium and zinc, inhibit the absorption oftetracycline and reduce availability. Doxycycline has a slightly lesser tendency to formchelates, thus milk reduces its bioavailability somewhat less than other tetracyclines.Availability of many drugs is determined by their solubility at the local pH. In thestomach this is highly variable, depending on the presence of food, but the small intestinehas a relatively constant pH around 7.0. Drug absorption may be modulated by the presenceof food which alters the gastric pH, the viscosity and the transit time through varioussections of the gut and a single clear effect may not be evident.Grapefruit juice greatly increases the bioavailability of certain drugs such as lovastatinand simvastatin, but not pravastatin 79 . The increase in bioavailability probably results fromdownregulation of CYP3A4 in the small intestine 80 . Hence large amounts of grapefruit juiceshould be avoided, or the dose of affected drugs should be reduced accordingly. The effectappears to be specific to grapefruit juice, since it cannot be reproduced with other citrusjuices such as orange juice. It has been suggested that the inhibitory effect of grapefruit juicemay be partially counteracted as it may also activate P-glycoprotein efflux of some drugs 81Vitamin effectsThe consumption of large amounts of certain vitamins (doses of 1 g or more) has becomepopular with the general public. High doses of vitamin C do not materially affect theclearance of oral antipyrine which might suggest that vitamin C is without action on drugmetabolism 82 ; however, vitamin C is excreted by conjugation with sulphate. Drugs which aremetabolised by sulphation such as ethinylestradiol would be likely to show competitiveeffects in their metabolism. Concomitant administration of ethinylestradiol with vitamin Cresulted in a 50% increase in the steady state concentration of the drug, effectivelyconverting a low dose oestrogen contraceptive pill to a high dose contraceptive pill 83 .Salt effectsIt has been postulated that changes in dietary salt might alter metabolism 82 . Volunteers feda high salt diet (400 mEq/day) compared to a low salt diet (10 mEq/day), during theadministration of oral quinidine demonstrated that the bioavialability of quinidine wasdecreased on the high salt diet 84 . The mechanism of this interaction remains unclearalthough it could involve an effect on transit or P-glycoprotein status.First-pass metabolismMetabolism of drugs administered orally may occur either by gut wall enzymes or by theliver. Hepatic or gut wall enzymes have a limited capacity and the metabolizing enzymes maynot necessarily be distributed evenly in the small intestinal epithelium. Estronesulphokinases. for example, are more prevalent in the duodenal mucosa than the ileum 85 .Thus, oestrogens released lower down in the intestine may reach the blood at more rapidrates and in larger amounts, than the same compounds released in the duodenum andjejunum.With the exception of the mouth and the terminal rectal area, the venous drainage ofthe gastrointestinal tract drains enters the liver via the portal vein. Thus, a fraction of theactive agent undergoes biotransformation by the liver before reaching the systemiccirculation and its site of action. Biotransformation generally inactivates drugs, but it can