The overall objective of this continuation Program Project remains the definition of determinants and the elucidation of mechanisms responsible for interindividual variability in response following drug administration in humans. The basic and clinical knowledge derived from the proposed research will provide a basis for the rational development and safe use of drugs. The Program Project's goals will be achieved by a synergistic group of investigators with expertise and interests in medicine, pharmacology, biochemistry, molecular biology and genetics. The focus of Project 20 is on cytochrome P4503A (CYP3A) which is involved in the metabolism of over 50 percent of drugs and is an important determinant of their first-pass metabolism following oral administration. Studies are proposed to investigate why the in vivo metabolism of various CYP3A substrates does not appear to correlate with each other despite the involvement of a common enzyme. Genetic factors contributing to interindividual variability in CYP3A activity will also be investigated in twin- and population studies. Project 21 will investigate whether pre-prescription genotyping of an individual patient will improve drug efficacy and safety. The anticoagulant warfarin, which has a narrow therapeutic index and is variably metabolized by polymorphic cytochrome P4502C9, will be used to test this possibility. The central theme of Project 22 is genetic variability in hepatic efflux transporters and orphan nuclear receptors involved in the transcription of cytochrome P4503A and the transporters. In addition to discovering novel polymorphisms, the functional consequences of such variability will also be assessed both in vitro and in vivo. Project 23 is directed towards the in vivo pharmacological modulation in humans of the function of the membrane efflux transporter MDR1 (P-glycoprotein) that is a determinant of the disposition of many drugs. The feasibility of using a potent and specific MDR1 inhibitor to increase tissue and systemic drug bioavailability will be specifically addressed.
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