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  • Discuss the roles that membrane transporters play in drug disposition and action.
  • Explain how drug transporters influence drug action in the intestine, liver, kidney, and blood–brain barrier.
  • Describe how pharmacogenetic changes in P-glycoprotein may affect drug concentrations and pharmacodynamics.
  • Provide examples of how pharmacogenetic variants may affect pharmacokinetics of substrate compounds for the following transporters: breast cancer resistance protein (BCRP), organic anion-transporting polypeptide 1B1 (OATP1B1), bile salt export pump (BSEP), organic cation transporter 1 (OCT1), organic cation transporter 2 (OCT2), and multidrug and toxin extrusion 1 (MATE1).

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Transporters are membrane proteins that are ubiquitous throughout the body functioning to control the influx of essential nutrients and ions and the efflux of cellular waste, toxins, and drugs. Transporters located in the liver, intestine, kidney, and blood–brain barrier (BBB) are of particular interest in drug development and utilization. Multiple transporters work in a coordinated fashion to transport endogenous and exogenous substances into and out of cells. In certain organs, such as the liver and intestine, transporters and drug-metabolizing enzymes work together to affect the pharmacokinetics of drugs.

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Transporters play an important role in drug disposition, therapeutic efficacy, adverse drug reactions, and drug–drug interactions. Multiple environmental and genetic factors may affect the variability of transporter expression. Understanding the contribution of genetic variability to transporter expression and phenotype may allow clinicians to individualize drug therapy based on genetic factors. There are two major superfamilies of transporters important in drug disposition: solute carrier (SLC) transporters, a family of passive and active transporters that rely on chemical and/or electrical gradients for transport, and ATP-binding cassette (ABC) transporters, a family of primary active transporters that are ATP dependent. The following drug transporters will be discussed in this chapter with respect to the current knowledge of their pharmacogenetics: P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion-transporting polypeptide (OATP1B1), bile salt export pump (BSEP), organic cation transporter 1 (OCT1), organic cation transporter 2 (OCT2), multidrug and toxin extrusion 1 (MATE1), and organic anion transporters 1 and 3 (OAT1 and OAT3). For a review of other transporters not covered in this chapter, the reader is referred to other references.1,2 For most drug transporters, clinical evidence is sparse or, in the case of P-gp, conflicting. Due to the complex nature of drug disposition and subsequent effect on clinical outcome, isolating clinically significant drug transporter genetic variants is a challenging endeavor.

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Most orally administered drugs are absorbed in the small intestine. Although the process of drug absorption is largely a passive process, transporters in the small intestine are determinants of the extent and variability of drug absorption that ultimately affect the pharmacokinetics of numerous drugs. Transporters expressed at the apical membrane of enterocytes may facilitate intestinal drug absorption or reduce the bioavailability of a drug. The resulting pharmacokinetic impact is dependent on the mechanism of transport. Transporters from both the ABC and SLC superfamilies are present in the apical membrane of the enterocyte (Figure 7–1...

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