The Cytochrome P450-3A (CYP3A) drug-metabolizing enzymes are responsible for the biotransformation and clearance of a large number of drugs used in contemporary clinical therapeutics. Individual variation in the expression and activity of CYP3A, both in the liver and gastrointestinal (GI) tract mucosa, appears to underlie much of the large individual variability in pharmacokinetics and response to therapeutically-administered medications that are CYP3A substrates. Many clinical studies demonstrate that age, gender, and ethnicity (race) may account for components of this variation in predictable ways. For example, some data suggest that clearance of certain CYP3A drugs: a Becomes reduced in old age; b Is higher in women than in men; c Is greater in African-Americans than in Caucasians. However the available data are not by any means consistent. Furthermore, variants in the CYP3A4, CYP3A5, and Pregnane-X receptor genes may modulate age-, gender-, or ethnicity-related variations in CYP3A function in ways that are not understood. This study will prospectively evaluate cohorts of young (18-45 years), """"""""young"""""""" elderly (60-69 years) and """"""""old"""""""" elderly (>70 years) volunteers, consisting of African-American and Caucasian men and women. The study paradigm will assess: a. Hepatic blood flow (HBF), based on clearance of low-dose intravenous lidocaine; b Pharmacokinetics and pharrnacodynamics of intravenous and oral midazolam, a """"""""pure"""""""" CYP3A substrate; c The prevalence of variants in the CYP3A4, CYP3A5, and pregnane-X receptor genes, using molecular genetic techniques; d. Plasma concentrations of biologically active testosterone. From a. and b., it is possible to estimate midazolam clearance by both routes, net oral bioavailability, and bioavailability attributable to hepatic and gastrointestinal presystemic extraction. With appropriate statistical techniques, the contributions of age, gender, and ethnicity to overall variance can be determined, as well as modulation of the relationships by genetic CYP3A variants and by biologically active testosterone. This study should provide important mechanistic information on the role of age, gender, and ethnicity as sources of variability in CYP3A-mediated drug metabolism and response.
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