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Organic Cation Transporters in Drug Disposition and Response

  • Author(s): Morrissey, Kari M.
  • Advisor(s): Giacomini, Kathleen M
  • et al.
Abstract

Transporters in the kidney play an important role in the tissue distribution and excretion of various prescription drugs and endogenous metabolic waste products. For organic cations that are dependent upon renal elimination, variability in the activities or expression levels of renal organic cation transporters are major sources of intra- and inter-individual variation in secretory clearance. The overall goal of this dissertation research was to enhance our knowledge of the clinical impact of renal organic cation transporters on variation in drug disposition and response. This research primarily focuses on the role of efflux transporters at the apical membrane of the renal proximal tubule: Multidrug and toxin extrusion proteins, MATE1 and MATE2K.

The studies described in this dissertation aimed to understand the importance of two potential sources of variability in renal drug handling: extrinsic (i.e., a drug-drug interaction mediated by MATE2K) and intrinsic (i.e., expression variants of MATE1 and MATE2K). Our in vitro and clincal data suggest that both MATE1 and MATE2K play important roles in the exposure, tissue distribution and response of the antidiabetic drug, metformin. Furthermore, these studies also challenge currently recommended methods and criteria for the conduct and use of in vitro experiments to inform the decision to perform a clinical investigation of a transporter-mediated drug-drug interaction. This dissertation research also demonstrates that expression variants of MATE1 and MATE2K have a clinical impact on the disposition and pharmacologic effects of metformin in healthy volunteers and type II diabetic subjects. Overall, the studies described in this dissertation add to our understanding of the role of MATE1 and MATE2K in renal drug handling and peripheral effects of drugs.

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