Enzyme kinetics for clinically relevant CYP inhibition.
In vitro cytochrome P450 (CYP)-associated metabolic studies have been considered cost-effective for predicting the potential clinical drug-drug interactions (DDIs), one of the major attritions in drug development. The breakthroughs during the past decade in understanding the biochemistry of CYP-mediated biotransformation and molecular biology of CYP gene regulation in humans have provided the scientific bases for such endeavors in early drug development. In this review, the enzyme kinetics of CYP inhibitions is described, with the primary focus on the ones proven with clinical relevance, namely the competitive inhibition and mechanism-based inactivation (MBI). Competitive CYP inhibition, the most often detected reversible inhibition, is well understood and has been studied extensively both in vitro and in clinical setting. Recently, MBI has received increasing attention. It has been recognized that MBI could occur more often than anticipated, due in part to the redox cycling-allied enzymatic action of CYPs. As commonly as an irreversible inhibition, MBI would inactivate the target proteins, and thus would be generally considered of high potential for causing clinical DDI. Moreover, the reversible inhibitions other than the competitive, namely noncompetitive, uncompetitive and mixed, were also documented for the important drug-metabolizing CYP members, particularly CYP1A2 and CYP2C9. Finally, the unusual kinetic interactions, which did not follow the Michaelis-Menten (M-M) kinetics, were detected in vitro for the majority of drug-metabolizing CYP members, and manifested for CYP3A4. However, the clinical relevance of the interactions involving the unusual CYP kinetics has not yet been fully understood. Nonetheless, the reversibility and inhibitory potency should be considered as the major determinants of the clinical relevance, particularly in combination with the therapeutic exposure levels. With rapid expansion of knowledge and technology, the evaluation of the clinically relevant CYP-associated DDIs in vitro is not only desirable but also achievable.
Drug Disposition, Eisai Research Institute, Andover, MA 01810, USA. zhi-yi_zhang@eri.eisai.com
Zhi-Yi
ZY
Zhang
Y Nancy
YN
Wong
D000818:Animals; D001665:Binding Sites / Q000502:physiology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000493:pharmacokinetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System