The Scientific Basis of Drug-Drug Interactions: Mechanism and Preclinical Evaluation
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THE SCIENTIFIC BASIS OF DRUG-DRUG INTERACTIONS: MECHANISM AND PRECLINICAL EVALUATION ALBERTP.LI, PHD Vice President, Hepatic Technologies, In Vitro Technologies, Inc., Baltimore, Maryland
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 inhibitorypotential for drugmetabolizing enzymes, and 3. Evaluation of the inductionpotential for drug-metabolizing enzymes. cDNA-expressed enzymes and microsomes are useful in the evaluation of metabolic pathways, especially in the identijkation of isozymes involved in metabolism. Microsomes, hepatocytes, and liver slices are useful in the evaluation of the inhibitorypotential 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. Key Words: Drug-drug interactions; In vitro systems; Human; Liver; Hepatocytes
MECHANISM AND CLINICAL SIGNIFICANCE OF PHARMACOKINETIC DRUG-DRUG INTERACTIONS
drug. Although pharmacokinetic drug-drug interactions can occur during absorption, distribution, and elimination phases following initial drug administration, interference with drug metabolism appears to te the predomiMULTIPLE DRUG THERAPY is widely nant mechanism. The interference can occur practiced to treat either a medical disorder via inhibition or induction of the metabolism or to treat several concurrently-existing ailof one drug by a coadministered drug. Both ments in the same patient. It is now known mechanisms of pharmacokinetic drug-drug that drugs may interact with each other, with interactions can have serious clinical conseserious pharmacological andor toxicological quences. consequences. Drugs interact mainly by a Inhibition of drug metabolism results in phenomenon known as pharmacokinetic drugan increase in plasmdtissue drug concentradrug interactions-alteration of the metations of administered drugs, which can lead bolic clearance of a drug by a coadministered to toxicity, especially with drugs that have a narrow therapeutic index. Thus, pharmacokinetic drug-drug interactions via the inhibiReprint address: Albert p. Li, pm, Vice Resident, Hepatic Technologies, In Vitro Technologies. Inc., tory mechanism are a safety concern- A wellestablished example of a drug-drug interac1450 South Rolling Road, Baltimore, M D 21227. 657 UNIVERSITY TSS on June 20, 2015 Downloaded from dij.sagepub.com at PURDUE
Albert P. Li
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tion via an inhibitory mechanism is the occurrence of torsades de point
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