Substrate-dependent modulation of the catalytic activity of CYP3A by erlotinib  

作　　者：Pei-pei DONG Zhong-ze FANG Yan-yan ZHANG Guang-bo GE Yu-xi MAO Liang-liang ZHU Yan-qing QU Wei LI Li-ming WANG Chang-xiao LIU Ling YANG 

机构地区：[1]Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China [2]Graduate University of Chinese Academy of Sciences, Beijing 100049, China [3]the Second Affiliated Hospital of Dalian Medical University, Dalian 116027, China [4]Tianjin Key Laboratory of Pharmacokinetics and Clinical Pharmacology, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China

出　　处：《Acta Pharmacologica Sinica》2011年第3期399-407,共9页中国药理学报（英文版）

基　　金：This work was supported by the National Natural Science Foundation of China （No 30630075, 30772608, 30973590, and 81072698）, the National Key Technology R＆D Program in the 11th Five-year Plan of China （No 2008ZX10002-019） and the National Science ＆ Technology Pillar Program of China （No 2009BADB9B02）.

摘　　要：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.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.

关 键 词：ERLOTINIB CYP isoform human liver microsomes substrate-dependent inhibition （or modulation） drug interaction 

分 类 号：Q55[生物学—生物化学] O643.36[理学—物理化学]