Through import and export mechanisms, transporters ultimately control the exposure of cells to chemical carcinogens, environmental toxins, and drugs and thereby play critical roles in the cellular toxicities of these agents. Transporter-mediated adverse drug responses generally can be classified into three categories (Figure 2-3).
Transporters expressed in the liver and kidney—as well as metabolic enzymes—are key determinants of drug exposure (Figure 2-3, top panel) because they control the total clearance of drugs and thus influence the plasma concentration profiles and subsequent exposure to the toxicological target.
Transporters expressed in tissues that may be targets for drug toxicity (e.g., brain) or in barriers to such tissues (e.g., the blood-brain barrier [BBB]) can tightly control local drug concentrations and thus control the drug exposure of these tissues (Figure 2-3, middle panel). Drug-induced toxicity sometimes is caused by the concentrative tissue distribution mediated by influx transporters.
Transporters for endogenous ligands may be modulated by drugs and thereby exert adverse effects (Figure 2-3, bottom panel). If severe, these effects can lead to withdrawal of the drug
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