Drug-drug interactions (DDIs) involving drug-metabolizing enzymes and membrane transporters can lead to alteration in substrate drug (victim) exposure, and can influence the pharmacological and toxicological effects. In order to predict DDI potential, it is important to quantitatively characterize the major enzyme(s) and/or transporter(s) involved in the clearance of drugs, in terms of fraction metabolized (fm) and fraction transported (ft). In this review, we discuss a strategy using Extended Clearance Classification System (ECCS) to identify the clearance mechanism(s) early in drug discovery, and subsequently rational staging of in vitro characterization to determine fm and ft. In addition, the examples of complex DDIs due to involvement of transporter-enzyme interplay in the hepatic clearance are discussed.
Keywords: Complex DDI; Drug-drug interaction (DDI); Extended clearance classification system (ECCS); Fraction metabolized (f(m)); Fraction transported (f(t)); Transporter-enzyme interplay.
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