Metabolism and Pharmacokinetics of Allitinib in Cancer Patients: The Roles of Cytochrome P450s and Epoxide Hydrolase in its Biotransformation
Abstract
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-of-flight mass spectrometry. The pharmacologically active α,β-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-S-transferase. 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.
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Allitinib effectively inhibits the EGFRT790M/L858R double mutant with an IC50 value of 12 nM.
“Allitinib effectively inhibits the EGFRT790M/L858R double mutant with an IC50 value of 12 nM.177–181”
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- Authors
- Lin, L., Xie, C., Gao, Z., Chen, X., & Zhong, D.
- Affiliations
- Chinese Academy of Sciences (CN)
- Venue
- Drug Metabolism and Disposition
- Publisher
- Elsevier BV
- Published
- 2014-05
- Volume
- 42
- Issue
- 5
- Pages
- 872-884
- ISSN
- 0090-9556 (ISSN-L)
- OpenAlex
- W2102711809
- Cited by
- 11
- References
- 29
- Citations by year
- 2023: 3 · 2022: 1 · 2021: 2 · 2017: 3 · 2015: 1 · 2014: 1
- FWCI
- 1.91
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Drug Metabolism and Disposition (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Eicosanoids and Hypertension Pharmacology
- Keywords
- drug metabolism, pharmacokinetics, cytochrome P450, epoxide hydrolase, EGFR tyrosine kinase inhibitors, metabolite identification, O-dealkylation, amide hydrolysis, glutathione conjugation, glutathione S-transferase, CYP3A4/5, CYP1A2, reactive intermediates, solid tumors
- MeSH terms
- Acrylamides, Antineoplastic Agents, Biotransformation, Chromatography, Liquid, Cytochrome P-450 Enzyme System, Epoxide Hydrolases, Feces, Female, Humans, Male, Microsomes, Liver, Neoplasms, Permeability, Quinazolines, Mass Spectrometry, Caco-2 Cells
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