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Substrate-dependent modulation of the catalytic activity of CYP3A by erlotinib
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Substrate-dependent modulation of the catalytic activity of CYP3A by erlotinib
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Journal Article
Substrate-dependent modulation of the catalytic activity of CYP3A by erlotinib
2011
Overview
Aim： To ascertain the effects of erlotinib on CYP3A, to investigate the amplitude and kinetics of erlotinib-mediated inhibition of seven major CYP isoforms in human liver microsomes （HLMs） for evaluating the magnitude of erlotinib in drug-drug interaction in vivo. Methods： The activities of 7 major CYP isoforms （CYPIA2, CYP2A6, CYP3A, CYP2Cg, CYP2D6, CYP2C8, and CYP2E1） were assessed in HLMs using HPLC or UFLC analysis. A two-step incubation method was used to examine the time-dependent inhibition of erlotinib on CYP3A. Results： The activity of CYP2C8 was inhibited with an IC50 value of 6.17±2.0 pmol/L. Erlotinib stimulated the midazolam l＇-hydroxy reaction, but inhibited the formation of 6β-hydroxytestosterone and oxidized nifedipine. Inhibition of CYP3A by erlotinib was substratedependent： the IC50 values for inhibiting testosterone 6β-hydroxylation and nifedipine metabolism were 31.3±8.0 and 20.5±5.3 μmol/L, respectively. Erlotinib also exhibited the time-dependent inhibition on CYP3A, regardless of the probe substrate used： the value of K＋ and kinact were 6.3 pmol/L and 0.035 min-1 for midazolam; 9.0 pmol/L and 0.045 min-1 for testosterone; and 10.1 μmol/L and 0.058 min^-1 for nifedipine, Conclusion： The inhibition of CYP3A by erlotinib was substrate-dependent, while its time-dependent inhibition on CYP3A was substrate- independent. The time-dependent inhibition of CYP3A may be a possible cause of drug-drug interaction, suggesting that attention should be paid to the evaluation of erlotinib＇s safety, especially in the context of combination therapy.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ CYP2D6
/ CYP3A
/ Cytochrome P-450 CYP3A - metabolism
/ Cytochrome P-450 CYP3A Inhibitors
/ Cytochrome P-450 Enzyme Inhibitors
/ Cytochrome P-450 Enzyme System - metabolism
/ Humans
/ Microsomes, Liver - drug effects
/ Microsomes, Liver - enzymology
/ Original
/ Protein Kinase Inhibitors - metabolism
/ Protein Kinase Inhibitors - pharmacology
/ Vaccine
/ 催化活性
/ 安全性评价
/ 时间依赖性
/ 药物相互作用
