RT Journal Article
SR Electronic
T1 Interaction of Lapatinib with Cytochrome P450 3A5
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.112.044958
DO 10.1124/dmd.112.044958
A1 Eric Chun Yong Chan
A1 Lee Sun New
A1 Teck Beng Chua
A1 Chun Wei Yap
A1 Han Kiat Ho
A1 Sidney D Nelson
YR 2012
UL http://dmd.aspetjournals.org/content/early/2012/04/17/dmd.112.044958.abstract
AB Lapatinib, an oral tyrosine kinase inhibitor used for breast cancer, has been reported to cause idiosyncratic hepatotoxicity. Recently, it has been found that lapatinib forms a metabolite-inhibitor complex (MIC) with CYP3A4 via the formation of an alkylnitroso intermediate. As CYP3A5 is highly polymorphic compared to CYP3A4 and also oxidizes lapatinib, we investigated the interactions of lapatinib with CYP3A5. Lapatinib inactivated CYP3A5 in a time-, concentration- and NADPH-dependent manner using testosterone as probe substrate with Ki and kinact values of 0.0376 mM and 0.0226 min-1, respectively. However, similar results were not obtained when midazolam was used as the probe substrate, suggesting that inactivation of CYP3A5 by lapatinib is site-specific. Poor recovery of CYP3A5 activity post-dialysis and the lack of a Soret peak confirmed that lapatinib does not form a MIC with CYP3A5. The reduced carbon monoxide (CO)-differential spectrum further suggested a large fraction of the reactive metabolite of lapatinib is covalently adducted to the apoprotein of CYP3A5. GSH trapping of a reactive metabolite of lapatinib formed by CYP3A5 confirmed the formation of quinoneimine-GSH adduct derived from the O-dealkylated metabolite of lapatinib. In silico docking studies supported the preferential formation of an O-dealkylated metabolite of lapatinib by CYP3A5 compared to an N-hydroxylation reaction that is predominantly catalyzed by CYP3A4. In conclusion, lapatinib appears to be a mechanism-based inactivator of CYP3A5 via adduction of a quinoneimine metabolite.