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(Section A: Molecular, Structural, and Cellular Biology of Drug Transporters) The Role of MDR1 Genetic Polymorphisms in Interindividual Variability in P-glycoprotein Expression and Function

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The human multidrug resistance gene (MDR1), spanning greater than 200 kb, encodes for the ATP-dependent membrane efflux transporter, P-glycoprotein (Pgp). Significant progress has been made in the discovery of MDR1 polymorphisms and the assessment of allelic frequencies. The search for key genetic determinants that predispose individuals to drugs that are substrates or inhibitors of Pgp has just begun. Reports in the literature, particularly focusing on the C3435T polymorphism, have provided discordant results with respect to functional modification in vitro, and Pgp expression and disposition of probe drugs in vivo. Due to the large size of the MDR1 gene, genotyping based on individual single nucleotide polymorphism (SNPs) analysis is not sufficient to predict functional consequences. Strong linkage disequilibrium has been detected between several MDR1 polymorphisms, and discrepancies in the literature may be due to the focus on the influence of single nucleotide variations instead of on linked nucleotide variations. Multiple SNPs found on the same chromosome are assigned to a specific haplotype, and some attempts have been made to determine the role of MDR1 haplotypes in Pgp variability. Most of the data for MDR1 haplotype have been predicted based on computational or mathematical models. However, molecular haplotyping techniques, analysis of linkages on the same chromosome directly by biophysical and biochemical means, may be needed to characterize haplotypes in individuals with a highly polymorphic and large gene like MDR1. Haplotype identification may prove to be vital in identifying the functional significance of MDR1 polymorphisms on disease susceptibility and drug disposition.
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Keywords: Haplotype; chromosome; nucleotide polymorphism; polymorphic

Document Type: Review Article

Affiliations: Department of Pharmaceutics, Box 357610, University of Washington, Seattle, WA, USA, influence pharmacokinetics and, in turn, pharmacodynamics.

Publication date: February 1, 2004

More about this publication?
  • Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism and disposition. The journal serves as an international forum for the publication of timely reviews in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the latest and most important developments. The journal covers the following areas:

    In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites and adducts.
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