THE EFFECTS OF DIET, AGING AND DISEASE-STATES ON PRESYSTEMIC ELIMINATION AND ORAL-DRUG BIOAVAILABILITY IN HUMANS

Presystemic metabolism occurring in the intestinal epithelium and/or l iver is frequently an important determinant of drug bioavailability af ter oral administration. Several factors are potentially involved in s uch a first-pass effect and their modulation may significantly contrib ute to intra-and interindividual variability in a drug's plasma concen tration-time curve. For example, macronutrient intake and nutritional status may alter cytochrome P-450 (CYP) metabolism by the liver, and f ood per se in the form of a meal can also affect the first-pass metabo lism of some drugs. More important changes, however, result from micro nutrients and non-nutrients present in food. In the case of charcoal-b roiled and smoked foods, polycyclic aromatic hydrocarbons formed durin g their preparation result in the induction of xenobiotic metabolizing enzymes, especially those regulated by the Ah-receptor, e.g. CYP1A, w hich are localized in the intestinal tract. A similar effect also occu rs following the ingestion of cruciferous vegetables like brussels spr outs and cabbage, which contain indole-related phytochemicals. Such in duction can markedly reduce a drug's oral bioavailability. By contrast , the glucosinolate breakdown products of other vegetables produce inh ibition of drug metabolism. In the case of phenethyl isothiocyanate-co ntaining watercress, CYP2E1 activity is markedly impaired; however, ot her organo-sulfur compounds present in, for example, garlic appear to have essentially no effect on drug metabolism. Constituents of grapefr uit juice also result in reduced first-pass metabolism, especially for drugs that are CYP3A substrates. Again, this dietary effect is more p ronounced in the intestinal epithelium than the liver. A similar, but more generalized, phenomenon also appears to be associated with eating piperine- and capsaicin-containing spices. Possible future applicatio ns of such metabolic inhibition include the use of active phytochemica ls as bioavailability enhancers for drugs exhibiting a large first-pas s effect, and also as cancer chemoprotective agents where CYP-mediated procarcinogen activation is a critical initial step in carcinogenesis . Aging results in a number of physiological changes that potentially can alter drug metabolism and presystemic elimination. By far the most important of these is a reduction in drug metabolizing enzyme activit y. Unfortunately, the extent of this effect appears to be unpredictabl e, both with respect to a specific drug as well as a particular indivi dual. However, the greatest age-related change in oral bioavailability and plasma concentrations is likely to occur with drugs that exhibit a significant first-pass effect (> 80%) in young subjects. A similar s ituation also appears to apply when liver disease is present, especial ly when this is severe. A further complication in such patients is the presence of vascular shunting, which leads to drug-containing blood b y-passing functional enzymes. As a result, plasma levels of drugs that normally exhibit marked first-pass metabolism may be many-fold higher in cirrhotic patients compared to those with normal liver function. ( C) 1997 Elsevier Science B.V.