Please use this identifier to cite or link to this item:
|Title:||Interaction of lapatinib with cytochrome P450 3A5||Authors:||Chan, E.C.Y.
|Issue Date:||Jul-2012||Citation:||Chan, E.C.Y., New, L.S., Chua, T.B., Yap, C.W., Ho, H.K., Nelson, S.D. (2012-07). Interaction of lapatinib with cytochrome P450 3A5. Drug Metabolism and Disposition 40 (7) : 1414-1422. ScholarBank@NUS Repository. https://doi.org/10.1124/dmd.112.044958||Abstract:||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. Because CYP3A5 is highly polymorphic compared with 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 a 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 postdialysis and the lack of a Soret peak confirmed that lapatinib does not form a MIC with CYP3A5. The reduced CO difference spectrum further suggested that 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 a 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 with 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. Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics.||Source Title:||Drug Metabolism and Disposition||URI:||http://scholarbank.nus.edu.sg/handle/10635/106069||ISSN:||00909556||DOI:||10.1124/dmd.112.044958|
|Appears in Collections:||Staff Publications|
Show full item record
Files in This Item:
There are no files associated with this item.
checked on Sep 21, 2019
WEB OF SCIENCETM
checked on Sep 13, 2019
checked on Sep 21, 2019
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.