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The Scientific Basis of Drug-Drug Interactions: Mechanism and Preclinical Evaluation

Pharmacokinetic drug-drug interactions (PDDI), in which the pharmacokinetic clearance of one drug is altered by a coadministered drug, can be divided mechanistically into two general categories: 1. Inhibitory PDDI—the inhibition of the metabolic clearance of one drug by a coadministered drug, and 2. Inductive PDDI—the enhancement of the metabolic clearance of one drug by a coadministered drug. Three mechanism-based approaches are commonly used in the evaluation of the drug-drug interaction potential of a drug: 1. Identification of metabolic pathways, 2. Evaluation of the inhibitory potential for drug-metabolizing enzymes, and 3. Evaluation of the induction potential for drug-metabolizing enzymes. cDNA-expressed enzymes and microsomes are useful in the evaluation of metabolic pathways, especially in the identification of isozymes involved in metabolism. Microsomes, hepatocytes, and liver slices are useful in the evaluation of the inhibitory potential of the drug in question. Currently, primary hepatocytes represent the most relevant and useful preclinical system for the evaluation of the induction potential of a drug.