ArticleDrug metabolism and disposition: the biological fate of chemicals2016
Cytochrome P450 3A4 and CYP3A5-Catalyzed Bioactivation of Lapatinib.
Article in Drug metabolism and disposition: the biological fate of chemicals, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 42 citations in OpenAlex.
- Advances in the design and discovery of small-molecule tyrosine kinase inhibitors for breast cancer.RSC advances · 2026Review
- Theoretical Study on the Metabolic Mechanism of Heptachlor in Human Cytochrome P450 Enzymes.International journal of molecular sciences · 2025Article
- Human Cytochrome P450 Cancer-Related Metabolic Activities and Gene Polymorphisms: A Review.Cells · 2024Review
- The Wnt/β-catenin signaling pathway plays a role in drug-induced liver injury by regulating cytochrome P450 2E1 expression.Toxicological research · 2023Article
- The role of cytochrome P450 3A4-mediated metabolism in sorafenib and lapatinib hepatotoxicity.Livers · 2023Article
- CYP2S1 and CYP2W1 expression is associated with patient survival in breast cancer.The journal of pathology. Clinical research · 2022Article
- Cytochrome P450-Catalyzed Metabolism of Cannabidiol to the Active Metabolite 7-Hydroxy-Cannabidiol.Drug metabolism and disposition: the biological fate of chemicals · 2021Article
- Intratumoural Cytochrome P450 Expression in Breast Cancer: Impact on Standard of Care Treatment and New Efforts to Develop Tumour-Selective Therapies.Biomedicines · 2021Review
- Detoxication versus Bioactivation Pathways of Lapatinib In Vitro: UGT1A1 Catalyzes the Hepatic Glucuronidation of Debenzylated Lapatinib.Drug metabolism and disposition: the biological fate of chemicals · 2021Article
- In vitro assessment of the photo(geno)toxicity associated with Lapatinib, a Tyrosine Kinase inhibitor.Archives of toxicology · 2021Article
- A mixture model to detect edges in sparse co-expression graphs with an application for comparing breast cancer subtypes.PloS one · 2021Article
- Biotransformation: Impact and Application of Metabolism in Drug Discovery.ACS medicinal chemistry letters · 2020Article
- Impact of cytochrome P450 variation on meperidineXenobiotica; the fate of foreign compounds in biological systems · 2020Article
- Protein Binding of Lapatinib and Its N- and O-Dealkylated Metabolites Interrogated by Fluorescence, Ultrafast Spectroscopy and Molecular Dynamics Simulations.Frontiers in pharmacology · 2020Article
- Novel 4-arylaminoquinazolines bearingJournal of enzyme inhibition and medicinal chemistry · 2019Article
- Interindividual Variation in CYP3A Activity Influences Lapatinib Bioactivation.Drug metabolism and disposition: the biological fate of chemicals · 2019Article
- Interaction between phytotherapy and oral anticancer agents: prospective study and literature review.Medical oncology (Northwood, London, England) · 2019Review
- Characterization of kinetics of human cytochrome P450s involved in bioactivation of flucloxacillin: inhibition of CYP3A-catalysed hydroxylation by sulfaphenazole.British journal of pharmacology · 2019Article
- Role of Cytochrome P450 Enzymes in the Metabolic Activation of Tyrosine Kinase Inhibitors.International journal of molecular sciences · 2018Review
- Cytochromes P450 1A2 and 3A4 Catalyze the Metabolic Activation of Sunitinib.Chemical research in toxicology · 2018Article
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
Metabolic activation of the dual-tyrosine kinase inhibitor lapatinib by cytochromes CYP3A4 and CYP3A5 has been implicated in lapatinib-induced idiosyncratic hepatotoxicity; however, the relative enzyme contributions have not been established. The objective of this study was to examine the roles of CYP3A4 and CYP3A5 in lapatinib bioactivation leading to a reactive, potentially toxic quinoneimine. Reaction phenotyping experiments were performed using individual human recombinant P450 enzymes and P450-selective chemical inhibitors. Lapatinib metabolites and quinoneimine-glutathione (GSH) adducts were analyzed using liquid chromatography-tandem mass spectrometry. A screen of cDNA-expressed P450s confirmed that CYP3A4 and CYP3A5 are the primary enzymes responsible for quinoneimine-GSH adduct formation using lapatinib or O-dealkylated lapatinib as the substrate. The mean kinetic parameters (Km and kcat) of lapatinib O-dealkylation revealed that CYP3A4 was 5.2-fold more efficient than CYP3A5 at lapatinib O-dealkylation (CYP3A4 kcat/Km = 6.8 μM(-1) min(-1) versus CYP3A5 kcat/Km = 1.3 μM(-1) min(-1)). Kinetic analysis of GSH adduct formation indicated that CYP3A4 was also 4-fold more efficient at quinoneimine-GSH adduct formation as measured by kcat (maximum relative GSH adduct levels)/Km (CYP3A4 = 0.0082 vs. CYP3A5 = 0.0021). In human liver microsomal (HLM) incubations, CYP3A4-selective inhibitors SR-9186 and CYP3cide reduced formation of GSH adducts by 78% and 72%, respectively, compared with >90% inhibition by the pan-CYP3A inhibitor ketoconazole. The 16%-22% difference between CYP3A- and CYP3A4-selective inhibition indicates the involvement of remaining CYP3A5 activity in generating reactive metabolites from lapatinib in pooled HLMs. Collectively, these findings support the conclusion that both CYP3A4 and CYP3A5 are quantitatively important contributors to lapatinib bioactivation.
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