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 liver is frequently an important determinant of drug bioavailability after oral administration. Several factors are potentially involved in such a first-pass effect and their modulation may significantly contribute to intra- and interindividual variability in a drug's plasma concentration-time curve. For example, macronutrient intake and nutritional status may alter cytochrome P-450 (CYP) metabolism by the liver, and food per se in the form of a meal can also affect the first-pass metabolism of some drugs. More important changes, however, result from micronutrients and non-nutrients present in food. In the case of charcoal-broiled and smoked foods, polycyclic aromatic hydrocarbons formed during their preparation result in the induction of xenobiotic metabolizing enzymes, especially those regulated by the Ah-receptor, e.g. CYP1A, which are localized in the intestinal tract. A similar effect also occurs following the ingestion of cruciferous vegetables like brussels sprouts and cabbage, which contain indole-related phytochemicals. Such induction can markedly reduce a drug's oral bioavailability. By contrast, the glucosinolate breakdown products of other vegetables produce inhibition of drug metabolism. In the case of phenethyl isothiocyanate-containing watercress, CYP2E1 activity is markedly impaired; however, other organo-sulfur compounds present in, for example, garlic appear to have essentially no effect on drug metabolism. Constituents of grapefruit juice also result in reduced first-pass metabolism, especially for drugs that are CYP3A substrates. Again, this dietary effect is more pronounced 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 applications of such metabolic inhibition include the use of active phytochemicals as bioavailability enhancers for drugs exhibiting a large first-pass 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 activity. Unfortunately, the extent of this effect appears to be unpredictable, both with respect to a specific drug as well as a particular individual. 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 situation also appears to apply when liver disease is present, especially when this is severe. A further complication in such patients is the presence of vascular shunting, which leads to drug-containing blood by-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.