Mechanism-based inactivation of cytochrome P450 3A4 by lapatinib.

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Teng WC, Oh JW, New LS, Wahlin MD, Nelson SD, Ho HK, Chan EC

Mechanism-based inactivation of cytochrome P450 3A4 by lapatinib.

Mol Pharmacol. 2010 Oct;78(4):693-703. doi: 10.1124/mol.110.065839. Epub 2010 Jul 12.

PubMed ID

20624855 [ View in PubMed

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Abstract

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 CYP3A4 by lapatinib as a possible cause of its idiosyncratic toxicity. Inhibition of CYP3A4 was time-, concentration-, and NADPH-dependent, with k(inact) = 0.0202 min(-1) and K(i) = 1.709 muM. 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 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 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, coincubation 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 quinoneimine that covalently modifies the CYP3A4 apoprotein and/or heme moiety.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Lapatinib	Cytochrome P450 2C8	Protein	Humans	Unknown	Substrate Inhibitor	Details
Lapatinib	Cytochrome P450 3A4	Protein	Humans	Unknown	Substrate Inhibitor	Details