Enhanced efflux of structurally-unrelated antineoplastic drugs from caner cells results in the multidrug resistance (MDR) phenotype, attributable to increased expression the MDR1 gene. The gene product, the drug efflux pump P-glycoprotein, has also been identified in normal tissues, and frequently co-localizes with members of the CYP superfamily responsible for drug metabolism, for example, CYP3A. In addition, it is now recognized that there is substantial overlap between the substrates of P-glycoprotein and CYP3A. Thus, the hypotheses to be tested in this Project have been formulated to determine the role of P-glycoprotein-mediated efflux in drug disposition by non-neoplastic tissues. Mammalian cells transfected by vaccinia with P-glycoprotein, CYP3A and their combination will be used to assess the extent to which P- glycoprotein-mediated transport of drugs of their metabolites determines apparent variability in the disposition of CYP3A substrates. In vivo studies indicate substantial variability in P- glycoprotein-mediated drug efflux, attributable to both allelic variants in the MDR1 gene and to variable expression of the transporter. Further identification, in vitro functional characterization, and population distribution of allelic variants will therefore be undertaken. Both in vitro and clinical data support an important role for P-glycoprotein-mediated transport of digoxin, which is not subject to extensive biotransformation.. Hence, to determine the extent of variability in P-glycoprotein-mediated transport in vivo, the population distribution of digoxin's renal tubular secretion and non-renal clearance will be determined in a large cohort of healthy subjects. Finally, we have isolated a partial clone which likely encodes the hepatic homolog of the another drug transporter, MRP (an MDR-related peptide). Studies are proposed to test the hypothesis that MRP HEP plays an important in hepatic drug transport. Drug transport is an increasingly recognized determinant of drug disposition; these studies will define mechanisms whereby variability in drug transport can contribute to variability in drug disposition.
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