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This review highlights the “interplay” between enzymes and transporters, essential components of eliminating organs for drug removal. The understanding of the interplay is important in terms of deciphering the change of one eliminatory pathway on compensatory mechanisms in drug disposal, and, ultimately, their importance in drug−drug interactions. Controversy existed on the explanation underlying the interplay between transporters and enzymes in the Caco-2 cell monolayer or cell culture systems, but less so on eliminating organs such as the intestine and liver. For the Caco-2 system, the increase in the mean residence time (MRT) accompanying increased secretion had been construed as the basis for increased metabolism. We hold the opposite view and assert that increased secretion should evoke a decrease in metabolism due to the competition between the enzyme and apical efflux transporter for the …