Details

Autor(en) / Beteiligte

• Dong, Pei-pei
• Fang, Zhong-ze
• Zhang, Yan-yan
• Ge, Guang-bo
• Mao, Yu-xi
• Zhu, Liang-liang
• Qu, Yan-qing
• Li, Wei
• Wang, Li-ming
• Liu, Chang-xiao
• Yang, Ling

Titel

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

Ist Teil von

• Acta pharmacologica Sinica, 2011-03, Vol.32 (3), p.399-407

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2011

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.