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INTRODUCTION

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Transporters are membrane proteins that are present in all organisms. These proteins control the influx of essential nutrients and ions and the efflux of cellular waste, environmental toxins, drugs, and other xenobiotics (Figure 5–1), consistent with their critical roles in cellular homeostasis, ~2000 genes in the human genome, ~7% of the total number of genes, code for transporters or transporter-related proteins. The functions of membrane transporters may be facilitated (equilibrative, not requiring energy) or active (requiring energy). In considering the transport of drugs, pharmacologists generally focus on transporters from 2 major superfamilies, ABC (ATP binding cassette) and SLC (solute carrier) transporters.

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Figure 5–1

Membrane transporters in pharmacokinetic pathways. Membrane transporters (T) play roles in pharmacokinetic pathways (drug absorption, distribution, metabolism, and excretion), thereby setting systemic drug levels. Drug levels often drive therapeutic and adverse drug effects.

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Most ABC proteins are primary active transporters, which rely on ATP hydrolysis to actively pump their substrates across membranes. Among the best recognized transporters in the ABC superfamily are P-glycoprotein (Pgp, encoded by ABCB1, also termed MDR1) and the cystic fibrosis transmembrane regulator (CFTR, encoded by ABCC7). The SLC superfamily includes genes that encode facilitated transporters and ion-coupled secondary active transporters. Forty-eight SLC families with ~315 transporters have been identified in the human genome. Many SLC transporters serve as drug targets or in drug absorption and disposition. Widely recognized SLC transporters include the serotonin transporter, SERT, and the dopamine transporter, DAT, both targets for antidepressant medications.

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MEMBRANE TRANSPORTERS IN THERAPEUTIC DRUG RESPONSES

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PHARMACOKINETICS. Transporters important in pharmacokinetics generally are located in intestinal, renal, and hepatic epithelia, where they function in the selective absorption and elimination of endogenous substances and xenobiotics, including drugs. Transporters work in concert with drug-metabolizing enzymes to eliminate drugs and their metabolites (Figure 5–2). In addition, transporters in various cell types mediate tissue-specific drug distribution (drug targeting). Conversely, transporters also may serve as protective barriers to particular organs and cell types. For example, P-glycoprotein in the blood-brain barrier protects the central nervous system (CNS) from a variety of structurally diverse drugs through its efflux mechanisms.

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Figure 5–2

Hepatic drug transporters. Membrane transporters (red ovals with arrows) work in concert with phase 1 and phase 2 drug-metabolizing enzymes in the hepatocyte to mediate the uptake and efflux of drugs and their metabolites.

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PHARMACODYNAMICS: TRANSPORTERS AS DRUG TARGETS. Membrane transporters are the targets of many clinically used drugs. SERT (SLC6A4) is a target for a major class of antidepressant drugs, the selective serotonin reuptake inhibitors (SSRIs). Other neurotransmitter reuptake transporters serve as drug targets for the tricyclic antidepressants, various amphetamines ...

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