The elderly (individuals over the age of 65) are the most medicated segment of society and account for 12% of the US population, increasing to 17% over the next 25 years. In part due to the polypharmacy that the elderly experience, there is a high incidence of drug-drug interactions in this group which is also particularly vulnerable to drug toxicity. A large number of commonly used drugs are eliminated from the body by oxidative metabolism catalyzed by the 3A sub-family of the cytochrome P450 (CYP) super family of enzymes. It is clear that for CYP3A substrates the systemic clearance is reduced and bioavailability increased in the elderly, but it is unclear whether these changes result in an increased potential for drug-drug interactions in the elderly. The bioavailability of CYP3A substrates is determined in large part by the extent of first-pass extraction of these drugs in the intestinal wall and the liver. The intestinal and hepatic CYP3A enzymes are independently regulated. Therefore the changes in clearance and bioavailability of CYP3A substrates observed in the elderly may reflect selective changes in the extraction drugs at intestinal and hepatic sites, which may in turn impact upon the incidence of drug-drug interactions in the elderly. This proposal will examine whether or not advanced age exaggerates the pharmacokinetic and pharmacodynamic outcome of drug-drug interactions. The effect of a CYP3A inhibitor (clarithromycin) and inducer (rifampin) on the intestinal availability, intestinal intrinsic clearance, hepatic availability and hepatic intrinsic clearance of midazolam will be quantified in young and elderly, male and female human volunteers. By means of a newly developed phenotyping procedure the investigators will examine whether the magnitude of the drug-drug interactions in these groups of human volunteers can be predicted by the dextromethorphan CYP3A urinary metabolic ratio. To directly address the hypothesis that aging and/or gender modulates intestinal CYP3A they will determine the amount, by immunoblotting, and catalytic activity of CYP3A in human duodenal biopsy tissue. Aging and gender differences in CYP3A activity will also be examined in a recently developed, chronically cannulated rat model. The latter approach allows a rigorous evaluation of 1) The extraction of CYP3A substrates by intestinal and hepatic first-pass sites in young, middle-aged and elderly rats of male and female genders. 2) The determinants of the magnitude of drug-drug interactions with CYP3A inhibitors and inducers in these animal groups. The intent of these studies is to provide a clear understanding of the mechanism of the interactions between midazolam and macrolide antibiotics in the elderly. However, the choice of model compounds will also provide a general understanding of the mechanism of interactions between CYP3A substrates and the modulation of these interactions by advanced age.
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