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

Abstract：

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 (CYP1A2, CYP2A6, CYP3A, CYP2C9, 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 IC(50) value of 6.17±2.0 μmol/L. Erlotinib stimulated the midazolam 1'-hydroxy reaction, but inhibited the formation of 6β-hydroxytestosterone and oxidized nifedipine. Inhibition of CYP3A by erlotinib was substrate-dependent: the IC(50) 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(I) and k(inact) were 6.3 μmol/L and 0.035 min(-1) for midazolam; 9.0 μmol/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.

journal_name

Acta Pharmacol Sin

journal_title

Acta pharmacologica Sinica

authors

Dong PP,Fang ZZ,Zhang YY,Ge GB,Mao YX,Zhu LL,Qu YQ,Li W,Wang LM,Liu CX,Yang L

doi

10.1038/aps.2010.218

subject

Has Abstract

pub_date

2011-03-01 00:00:00

pages

399-407

issue

3

eissn

1671-4083

issn

1745-7254

pii

aps2010218

journal_volume

32

pub_type

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