Human Metabolism of Lapatinib, a Dual Kinase Inhibitor: Implications for Hepatotoxicity

Castellino, Stephen; O'Mara, Michael J; Koch, Kevin M.; Borts, David J.; Bowers, Gary; MacLauchlin, Christopher

doi:10.1124/dmd.111.040949

Cited by 89 publications

(104 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3, HLM, rCYP3A4, and rCYP3A5 all converted lapatinib to 10 components (M1 through M10). Consistent with the results of previous in vitro (Teng et al, 2010) and in vivo studies (Castellino et al, 2012), the primary metabolites of lapatinib (M1, M3, M4, M8, and M10) were formed by N-dealkylation (M4 and M10), O-dealkylation (M1), N-hydroxylation (M8), or C-hydroxylation (M3). These and other oxidation reactions converted the five primary metabolites to four secondary metabolites (M2, M5, M6, and M7) and one tertiary metabolite (M9), as shown in Fig.…”

Section: Resultssupporting

confidence: 78%

“…Lapatinib was recently identified as an irreversible inhibitor of CYP3A5 (Chan et al, 2012) and a quasi-irreversible inhibitor of CYP3A4; the latter is associated with the formation of a ;455-nm absorbing MI complex (Takakusa et al, 2011). In addition, several stable Noxygenation metabolites of lapatinib have been reported both in vitro (Takakusa et al, 2011) and in vivo (Castellino et al, 2012). These findings suggest that lapatinib is converted to a nitroso metabolite that complexes with ferrous CYP3A4 (but not CYP3A5) and that the intervening metabolites might be sufficiently stable to provide information on the metabolic pathway leading to nitroso formation.…”

Section: Introductionmentioning

confidence: 99%

“…There are several reports linking lapatinib use with drug-induced liver injury (Gomez et al, 2008;Peroukides et al, 2011;Spraggs et al, 2012), and lapatinib carries a black box warning. The metabolism of lapatinib in vivo involves both N-and O-dealkylation by CYP3A4, CYP3A5, and to a lesser extent, CYP2C19 and CYP2C8 (Castellino et al, 2012). Lapatinib was recently identified as an irreversible inhibitor of CYP3A5 (Chan et al, 2012) and a quasi-irreversible inhibitor of CYP3A4; the latter is associated with the formation of a ;455-nm absorbing MI complex (Takakusa et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Metabolism-Dependent Inhibition of CYP3A4 by Lapatinib: Evidence for Formation of a Metabolic Intermediate Complex with a Nitroso/Oxime Metabolite Formed via a Nitrone Intermediate

et al. 2013

View full text Add to dashboard Cite

Metabolism-dependent inhibition (MDI) of cytochrome P450 (P450) enzymes has the potential to cause clinically relevant drug-drug interactions. In the case of several alkylamine drugs, MDI of P450 involves formation of a metabolite that binds quasi-irreversibly to the ferrous heme iron to form a metabolic intermediate (MI) complex. The specific metabolites coordinately bound to ferrous iron and the pathways leading to MI complex formation are the subject of debate. We describe an approach combining heme iron oxidation with potassium ferricyanide and metabolite profiling to probe the mechanism of MI complex-based CYP3A4 inactivation by the secondary alkylamine drug lapatinib. Ten metabolites formed from lapatinib by CYP3A4-mediated heteroatom dealkylation, Chydroxylation, N-oxygenation with or without further oxidation, or a combination thereof, were detected by accurate mass spectrometry. The abundance of one metabolite, the N-dealkylated nitroso/ oxime lapatinib metabolite (M9), correlated directly with the prevalence or the disruption of the MI complex with CYP3A4. Nitroso/ oxime metabolite formation from secondary alkylamines has been proposed to occur through two possible pathways: (1) sequential N-dealkylation, N-hydroxylation, and dehydrogenation (primary hydroxylamine pathway) or (2) N-hydroxylation with dehydrogenation to yield a nitrone followed by N-dealkylation (secondary hydroxylamine pathway). All intermediates for the secondary hydroxylamine pathway were detected but the primary N-hydroxylamine intermediate of the primary hydroxylamine pathway was not. Our findings support the mechanism of lapatinib CYP3A4 inactivation as MI complex formation with the nitroso metabolite formed through the secondary hydroxylamine and nitrone pathway, rather than by N-dealkylation to the primary amine followed by N-hydroxylation and dehydrogenation as is usually assumed.

show abstract

Section: Resultssupporting

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Metabolism-Dependent Inhibition of CYP3A4 by Lapatinib: Evidence for Formation of a Metabolic Intermediate Complex with a Nitroso/Oxime Metabolite Formed via a Nitrone Intermediate

et al. 2013

View full text Add to dashboard Cite

show abstract

“…Besides, our data provided a new therapy strategy for treatments of patients overexpressing MRP1. In addition, lapatinib is metabolized by human liver P450s to form O-and N-dealkylated metabolites (52). Some reports showed that lapatinib was an irreversible inhibitor of CYP3A4 and formed a metabolic intermediate (MI) complex with the latter, and the inhibition of CYP3A4 is a major cause of drug-to-drug interactions (53,54).…”

Section: Discussionmentioning

confidence: 99%

Lapatinib Antagonizes Multidrug Resistance-Associated Protein 1-Mediated Multidrug Resistance by Inhibiting Its Transport Function

Lin

Wang

et al. 2014

Mol Med

View full text Add to dashboard Cite

Lapatinib, a tyrosine kinase inhibitor, is used in the treatment of advanced or metastatic breast cancer overexpressing human epidermal receptor 2 (HER2). Lapatinib can modulate the function of ATP-binding cassette (ABC) transporters (ABCB1 and ABCG2), which are the major mechanism responsible for multidrug resistance (MDR) in cancer. In this study, we investigated the effect of lapatinib on multidrug resistance-associated protein 1 (MRP1 [ABCC1]), MRP2 (ABCC2), MRP4 (ABCC4) and lung relative resistance protein (LRP) drug efflux pumps. We demonstrated that lapatinib could enhance the efficacy of conventional chemotherapeutic agents in MRP1-overexpressing cells in vitro and in vivo, but no effect in MRP2-, MPR4-and LRP-overexpressing cells. Furthermore, lapatinib significantly increased the accumulation of rhodamine 123 (Rho123) and doxorubicin (DOX) in MRP1-overexpressing cells. However, lapatinib did not alter the protein or mRNA expression levels of MRP1. Further studies showed that the level of phosphorylation of AKT and extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) were not altered at the indicated concentrations of lapatinib. In conclusion, lapatinib enhanced the efficacy of conventional chemotherapeutic agents in MRP1-overexpressing cells by inhibiting MRP1 transport function without altering the level of AKT or ERK1/2 phosphorylation. These findings will encourage the clinical research of lapatinib combined with conventional chemotherapeutic drugs in MRP1-overexpressing cancer patients.

show abstract

“…9. Allitinib shared several metabolic pathways with its analog lapatinib (Castellino et al, 2012), including the O-dealkylation and hydroxylation of the quinazoline moiety. However, the major metabolic sites of allitinib are located at the a,b-unsaturated carbonyl group, and include amide hydrolysis and dihydrodiol formation.…”

Section: Metabolism Of Allitinib In Humans 881mentioning

confidence: 99%

Metabolism and Pharmacokinetics of Allitinib in Cancer Patients: The Roles of Cytochrome P450s and Epoxide Hydrolase in its Biotransformation

et al. 2014

View full text Add to dashboard Cite

Allitinib, a novel irreversible selective inhibitor of the epidermal growth factor receptor (EGFR) 1 and human epidermal receptor 2 (ErbB2), is currently in clinical trials in China for the treatment of solid tumors. It is a structural analog of lapatinib but has an acrylamide side chain. Sixteen metabolites of allitinib were detected by ultra-high-performance liquid chromatography/quadrupole time-offlight mass spectrometry. The pharmacologically active a,b-unsaturated carbonyl group was the major metabolic site. The metabolic pathways included O-dealkylation, amide hydrolysis, dihydrodiol formation, hydroxylation, and secondary phase 2 conjugation. The metabolite of amide hydrolysis (M6) and 27,28-dihydrodiol allitinib (M10) were the major pharmacologically active metabolites in the circulation. The steady-state exposures to M6 and M10 were 11% and 70% of that of allitinib, respectively. The biotransformation of allitinib was determined using microsomes and recombinant metabolic enzymes. In vitro phenotyping studies demonstrated that multiple cytochrome P450 (P450) isoforms, mainly CYP3A4/5 and CYP1A2, were involved in the metabolism of allitinib. Thiol conjugates (M14 and M16) and dihydrodiol metabolites (M5 and M10) were detected in humans, implying the formation of reactive intermediates. The formation of a glutathione conjugate of allitinib was independent of NADPH and P450 isoforms, but was catalyzed by glutathione-Stransferase. P450 enzymes and epoxide hydrolase were involved in M10 formation. Overall, our study showed that allitinib was metabolized by the O-dealkylation pathway similar to lapatinib, but that amide hydrolysis and the formation of dihydrodiol were the dominant metabolic pathways. The absorbed allitinib was extensively metabolized by multiple enzymes.

show abstract

Human Metabolism of Lapatinib, a Dual Kinase Inhibitor: Implications for Hepatotoxicity

Cited by 89 publications

References 27 publications

Metabolism-Dependent Inhibition of CYP3A4 by Lapatinib: Evidence for Formation of a Metabolic Intermediate Complex with a Nitroso/Oxime Metabolite Formed via a Nitrone Intermediate

Metabolism-Dependent Inhibition of CYP3A4 by Lapatinib: Evidence for Formation of a Metabolic Intermediate Complex with a Nitroso/Oxime Metabolite Formed via a Nitrone Intermediate

Lapatinib Antagonizes Multidrug Resistance-Associated Protein 1-Mediated Multidrug Resistance by Inhibiting Its Transport Function

Metabolism and Pharmacokinetics of Allitinib in Cancer Patients: The Roles of Cytochrome P450s and Epoxide Hydrolase in its Biotransformation

Contact Info

Product

Resources

About