PT  - JOURNAL ARTICLE
AU  - Woon Chien Teng
AU  - Jing Wen Oh
AU  - Lee Sun New
AU  - Michelle D Wahlin
AU  - Sidney D. Nelson
AU  - Han Kiat Ho
AU  - Eric Chun Yong Chan
TI  - Mechanism-Based Inactivation of Cytochrome P450 3A4 by Lapatinib
AID  - 10.1124/mol.110.065839
DP  - 2010 Jul 12
TA  - Molecular Pharmacology
PG  - mol.110.065839
4099  - http://molpharm.aspetjournals.org/content/early/2010/07/12/mol.110.065839.short
4100  - http://molpharm.aspetjournals.org/content/early/2010/07/12/mol.110.065839.full
AB  - Fatalities stemming from hepatotoxicity associated with the clinical use of lapatinib (Tykerb), an oral dual tyrosine kinase inhibitor (ErbB-1 and ErbB-2) used in the treatment of metastatic breast cancer, have been reported. We investigated the inhibition of cytochrome P450 3A4 (CYP3A4) by lapatinib as a possible cause of its idiosyncratic toxicity. Inhibition of CYP3A4 was time-, concentration-, and NADPH-dependent, with kinact=0.0202 min-1 and Ki=1.709 μM. The partition ratio was approximately 50.9. Addition of GSH did not affect the rate of inactivation. Testosterone protected CYP3A4 from inactivation by lapatinib. The characteristic Soret peak associated with a metabolite-intermediate complex (MIC) was not observed for lapatinib during spectral difference scanning. However, reduced carbon monoxide (CO)-difference spectroscopy did reveal a 43% loss of the spectrally detectable CYP3A4-CO complex in the presence of lapatinib. Incubation of either lapatinib or its dealkylated metabolite with human liver microsomes (HLM) in the presence of GSH resulted in the formation of a reactive metabolite (RM)-GSH adduct derived from the O-dealkylated metabolite of lapatinib. In addition, co-incubation of lapatinib with ketoconazole inhibited the formation of the RM-GSH adduct. In conclusion, we demonstrated for the first time that lapatinib is a mechanism-based inactivator of CYP3A4 most likely via the formation and further oxidation of its O-dealkylated metabolite to a quinone imine that covalently modifies the CYP3A4 apoprotein and/or heme moiety.