Abstract
Determining drug-metabolizing enzyme activities on an individual basis is an important component of personalized medicine, and cytochrome P450 enzymes (CYPs) play a principal role in hepatic drug metabolism. Herein, a simple method for predicting the major CYP-mediated drug clearance in vitro and in vivo is presented. Ten CYP-mediated drug metabolic activities in human liver microsomes (HLMs) from 105 normal liver samples were determined. The descriptive models for predicting the activities of these CYPs in HLMs were developed solely on the basis of the measured activities of a smaller number of more readily assayed CYPs. The descriptive models then were combined with the Conventional Bias Corrected in vitro–in vivo extrapolation method to extrapolate drug clearance in vivo. The Vmax, Km, and CLint of six CYPs (CYP2A6, 2C8, 2D6, 2E1, and 3A4/5) could be predicted by measuring the activities of four CYPs (CYP1A2, 2B6, 2C9, and 2C19) in HLMs. Based on the predicted CLint, the values of CYP2A6-, 2C8-, 2D6-, 2E1-, and 3A4/5-mediated drug clearance in vivo were extrapolated and found that the values for all five drugs were close to the observed clearance in vivo. The percentage of extrapolated values of clearance in vivo which fell within 2-fold of the observed clearance ranged from 75.2% to 98.1%. These findings suggest that measuring the activity of CYP1A2, 2B6, 2C9, and 2C19 allowed us to accurately predict CYP2A6-, 2C8-, 2D6-, 2E1-, and 3A4/5-mediated activities in vitro and in vivo and may possibly be helpful for the assessment of an individual’s drug metabolic profile.
Highlights
As the principal class of hepatic drug metabolizing enzymes, cytochrome P450 enzyme (CYP) play a critically important role in the biosynthesis and degradation of endogenous compounds and the metabolism of drugs and environmental procarcinogens [1]
The results show that the descriptive models of Vmax and intrinsic clearance (CLint) of all ten CYPs and Km of six CYPs (CYP1A2, 2B6, 2C9, 2C19, and 3A4/5) could be developed, and the essential structures of these models consisted of the measured Vmax, CLint, and Km of CYPs
The results indicate that the six CYPs (CYP2A6, 2C8, 2D6, 2E1, and 3A4/5)-mediated metabolic activities in vitro could be predicted if the activities of four CYPs (CYP1A2, 2B6, 2C9, and 2C19) measured in vitro were known
Summary
As the principal class of hepatic drug metabolizing enzymes, CYPs play a critically important role in the biosynthesis and degradation of endogenous compounds and the metabolism of drugs and environmental procarcinogens [1]. Interindividual variation in drug metabolism, which encompasses genetic polymorphisms of CYPs [2,3], smoking [2,3], drinking [2,3], age [4], and gender [5,6], has a substantial impact on individual drug safety and efficacy, raising a challenge to guide individualized medicine It is usually agreedthat patient differences in pharmacokinetics largely result from differences in the activities of an individual’s drug metabolizing enzymes, and is the chief reason for different responses to drugs [7,8,9]. Having information on the CLH is a necessary condition for individual dosage regimens
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