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Genetic Variation in Drug Transporters in Ethnic Populations

  • Author(s): Cropp, Cheryl
  • Advisor(s): Giacomini, Kathleen M.
  • et al.
Abstract

Drug metabolizing enzymes and membrane transporters work together in the absorption and disposition of drugs. Although the effects of ethnicity on drug metabolism are well studied, less is known about the ethnic differences in disposition of drugs that are substrates of membrane transporters. Organic anion transporters (OATs) are members of the SLC22 drug transporter family. OATs typically transport a wide variety of endogenous and xenobiotic organic anions. The goals of this dissertation were to determine the ethnic differences in allele frequencies of OAT2 (SLC22A7) and OAT3 (SLC22A8) variants and to determine if genetic variants of OAT2 and OAT3 impact the ability of these transporters to interact with drugs and endogenous substances. We showed that OAT2 is a novel, bidirectional, facilitative plasma membrane transporter for cGMP and other guanine nucleotides. cGMP exhibited a 50- to 100-fold enhanced uptake in OAT2 transfected cells over empty vector transfected cells. We observed that acyclovir, a guanine-like antiviral agent, was also an excellent substrate of OAT2. We sequenced the coding region of OAT2 in a collection of 272 DNA samples from an ethnically diverse cohort. Six rare non-synonymous variants were identified in the 272 DNA samples, suggesting that OAT2 is under strong negative selective pressure. Only Thr110Ile was polymorphic, with an allele frequency of 2.3% in African Americans. Acyclovir exhibited a significantly reduced uptake and Vmax in cells expressing Thr110Ile, in comparison to cells expressing the reference OAT2. OAT3, highly expressed in the basolateral membrane of renal proximal tubules, plays a significant role in the clearance of methotrexate, an anti-cancer and anti-inflammatory drug. We characterized the impact of OAT3 and its genetic variants on the transport of methotrexate and its metabolite, 7-hydroxymethotrexate. We showed that several OAT3 protein-altering variants exhibit significant differences in methotrexate transport compared to OAT3 reference in cellular assays. Genetic variants of OAT3 may contribute to inter-individual variation in methotrexate elimination and toxicity. These studies have led to an enhanced understanding of the role of OAT2, OAT3, and their genetic variants. The knowledge gained in this dissertation research will inform future clinical studies aimed at optimizing drug therapies in ethnically diverse populations.

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