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

Acta Pharmacol Sin. 2011 Mar;32(3):399-407. doi: 10.1038/aps.2010.218.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cytochrome P-450 CYP3A / metabolism
  • Cytochrome P-450 CYP3A Inhibitors*
  • Cytochrome P-450 Enzyme Inhibitors*
  • Cytochrome P-450 Enzyme System / metabolism
  • Drug Interactions
  • Erlotinib Hydrochloride
  • Humans
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Quinazolines / metabolism
  • Quinazolines / pharmacology*


  • Cytochrome P-450 CYP3A Inhibitors
  • Cytochrome P-450 Enzyme Inhibitors
  • Protein Kinase Inhibitors
  • Quinazolines
  • Cytochrome P-450 Enzyme System
  • Erlotinib Hydrochloride
  • Cytochrome P-450 CYP3A