Mechanism-based inactivation of cytochrome P450 3A4 by lapatinib

Molecular Pharmacology
Woon Chien TengEric Chun Yong Chan

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 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 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 ...Continue Reading

References

Mar 1, 1984·Proceedings of the National Academy of Sciences of the United States of America·D C DahlinS D Nelson
Jul 13, 1981·Life Sciences·J A HinsonJ R Gillette
Jan 1, 1995·Methods in Enzymology·R B Silverman
Jan 1, 1995·Clinical Pharmacology and Therapeutics·S A SpinlerS L Charland
May 5, 1998·Chemical Research in Toxicology·K HeP F Hollenberg
Mar 22, 2002·The Journal of Pharmacology and Experimental Therapeutics·Hsia-lien LinPaul F Hollenberg
Aug 2, 2006·Annual Review of Pharmacology and Toxicology·Jack Uetrecht
Sep 19, 2006·European Journal of Pharmacology·Kevin B ParkDominic P Williams
Feb 13, 2007·International Journal of Gynecological Cancer : Official Journal of the International Gynecological Cancer Society·M A SovakC Aghajanian
Jun 2, 2007·Expert Opinion on Drug Metabolism & Toxicology·Thomas M Polasek, John O Miners
Jul 7, 2007·Critical Reviews in Toxicology·Yasuhiro Masubuchi, Toshiharu Horie
Jul 31, 2007·British Journal of Clinical Pharmacology·Thomas M Polasek, John O Miners
May 7, 2008·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Henry L GomezGeorge W Sledge
Sep 23, 2008·Clinical Therapeutics·Patrick J Medina, Susan Goodin
Mar 14, 2009·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Xiaohai LiTomas Vojkovsky
Aug 8, 2009·Nature Protocols·F Peter GuengerichQian Cheng

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Citations

Mar 1, 2012·Breast Cancer Research and Treatment·Yi Ling TeoAlexandre Chan
Mar 3, 2011·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Hideo TakakusaSidney D Nelson
Apr 6, 2012·The Oncologist·Frans L OpdamJan H M Schellens
Oct 28, 2010·Drug Metabolism and Pharmacokinetics·Thomas A Baillie, Allan E Rettie
Jul 24, 2014·Carcinogenesis·Roumen BalanskySilvio De Flora
May 23, 2012·Expert Opinion on Drug Discovery·Amit S Kalgutkar, Deepak K Dalvie
Sep 7, 2011·Drug Metabolism Reviews·Dominique PessayreAbdellah Mansouri
Feb 3, 2015·Drug Metabolism Reviews·Han Kiat HoEric Chun Yong Chan
Nov 18, 2014·Expert Opinion on Drug Metabolism & Toxicology·Yi Ling TeoAlexandre Chan
Nov 21, 2014·Drug Metabolism Reviews·Thomas A Baillie
Oct 14, 2014·Journal of Pharmaceutical Sciences·Jie ShaoGuohua An
Oct 27, 2012·Cancer Treatment Reviews·Yi Ling TeoAlexandre Chan
Jan 2, 2016·Pharmacological Reviews·Janne T BackmanPertti J Neuvonen
Mar 10, 2016·Chemical Research in Toxicology·Marsha Rebecca EnoMichael D Cameron
Jul 3, 2015·Nutrition and Cancer·Angelika KaczyńskaAnna Herman-Antosiewicz
Oct 9, 2014·Annual Review of Pharmacology and Toxicology·Amit S Kalgutkar, Deepak Dalvie
May 28, 2016·Expert Opinion on Drug Safety·Bruno VincenziGiuseppe Tonini
Jul 28, 2016·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Joanna K TowlesKlarissa D Jackson
Oct 1, 2016·Chemical Research in Toxicology·Arun TailorB Kevin Park
Nov 3, 2016·Chemical Research in Toxicology·Monday O OgeseDean J Naisbitt
Nov 4, 2017·Cancer Chemotherapy and Pharmacology·Kevin M KochLionel D Lewis
Sep 14, 2018·Drug Metabolism Letters·Muthusamy Ramesh, Prasad V Bharatam
Jan 31, 2014·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Yedong WangHongjian Zhang
Mar 7, 2014·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Lishan LinDafang Zhong
Sep 25, 2014·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Jianmei WuJing Li
Oct 4, 2011·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Stephen CastellinoChristopher MacLauchlin
Apr 19, 2012·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Eric Chun Yong ChanSidney D Nelson
Oct 3, 2014·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Amanda K BollesLaura Lowe Furge
Aug 26, 2020·Expert Opinion on Drug Metabolism & Toxicology·Gabriel TaoRomi Ghose
Aug 15, 2018·International Journal of Molecular Sciences·Klarissa D JacksonMatthew J Vergne
Aug 8, 2015·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Vamshi K MandaShabana I Khan
Jan 12, 2017·BioMed Research International·Madison Davis, Brendan D Stamper

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