Application of Human Liver Microsomes in Metabolism-Based Drug-Drug Interactions: In Vitro-in Vivo Correlations and the Abbott Laboratories Experience

Abstract

Publisher Summary It is now known that most of the drug-metabolizing enzyme (DME) systems present in the human liver, for example, cytochrome P450, CYP; UDP-glucuronosyltransferase, UDPGT; Nacetyltransferase, NAT; and NADPH-dependent flavin-containing monooxygenase, FMO are composed of two or more enzymes or “isforms” that can differentially interact with any number of drugs. A well-managed drug-drug interaction, as in the case of ketoconazole and cyclosporin, can potentially be of economic benefit to the patient. Likewise, a potent interaction with an enzyme such as CYP can lead to autoinhibition of metabolism and superior pharmacokinetics. In vitro drug-drug interaction screening is fast becoming a standardized part of the drug development process and, depending on the particular pharmaceutical company and/or NDE, can be performed prospectively, concurrently, or respectively. In most cases, in vitro studies focus on the human liver microsomal CYP “superfamily” of proteins, as our present understanding of this system exceeds that of other DME systems. As the procedures for phenotyping and/or genotyping of clinical subjects become more readily available, in vivo confirmation of the polymorphic oxidations will be greatly facilitated. There is no all-encompassing in vitro and/or in vivo animal model for predicting drug-drug interactions in humans. Because the liver is considered to be the major site of metabolism, most investigators now find themselves routinely performing in vitro human metabolism studies with various combinations of primary cultured hepatocytes, precision-cut liver slices, banks of liver microsomes, and/or cDNA-expressed enzymes.