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Identification and Characterization of Dacomitinib Metabolites in Rats by Liquid Chromatography Combined With
Yayun Zhou1, Jiming Sha1, Biao Xu1
1Department of Thoracic Surgery The Second Affiliated Hospital of Anhui Medical University, Hefei, China.
Abstract:
Dacomitinib is an irreversible inhibitor targeting epidermal growth factor receptor, which has been developed for the treatment of metastatic non-small cell lung cancer (NSCLC). The aim of this study was to establish a reliable liquid chromatography combined with high resolution mass spectrometric method to identify and characterize the metabolites of dacomitinib in rats. In vitro metabolism was investigated through 60-min incubation with rat liver microsomes, while in vivo analysis involved bile and urine sample collection following a single oral 10 mg/kg dose. A total of 18 metabolites, were structurally elucidated through accurate MS measurements, MS2 spectral interpretation, and fragmentation pattern analysis, including two GSH conjugates and two N-acetyl-cysteine conjugates. Among these metabolites, a total of 12 metabolites were first reported, i.e., M1, M2, M3, M7, M9, M10, M11, M13, M14, M15, M16, and M17. The parent drug remained the predominant species across all metrices. The primary metabolic pathways included: oxidative defluorination, O-demethylation, N-dealkylation, oxidative deamination, piperidin ring opening, N-oxygenation, lactam formation, dehydrogenation, and hydroxylation. Phase II biotransformation pathways included GSH conjugation and N-acetyl-cysteine conjugation. These findings enhance understanding of dacomitinib's metabolic fate, providing critical insights into its elimination mechanisms, and supporting subsequent evaluation of therapeutic efficacy and safety profiles.
Insights
This study identified 18 dacomitinib metabolites in rats using LC-HRMS, revealing key metabolic pathways and aiding in understanding drug elimination for non-small cell lung cancer treatment.
Area of Science:
- Pharmacology
- Metabolism Studies
- Analytical Chemistry
Background:
- Dacomitinib is an irreversible EGFR inhibitor for metastatic non-small cell lung cancer (NSCLC).
- Understanding dacomitinib's metabolic fate is crucial for its clinical efficacy and safety.
Purpose of the Study:
- To establish a robust LC-HRMS method for identifying and characterizing dacomitinib metabolites in rats.
- To elucidate the metabolic pathways and elimination mechanisms of dacomitinib.
Main Methods:
- In vitro incubation with rat liver microsomes.
- In vivo analysis of bile and urine samples after oral dacomitinib administration.
- Liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS) for metabolite identification and structural elucidation.
Main Results:
- 18 dacomitinib metabolites were identified and structurally characterized, including 12 novel metabolites.
- The parent drug was the predominant species observed.
- Major metabolic pathways involved oxidation, dealkylation, ring opening, and Phase II conjugation (GSH and N-acetyl-cysteine).
Conclusions:
- The study successfully characterized dacomitinib metabolites and elucidated its metabolic fate in rats.
- Findings provide critical insights into dacomitinib's elimination mechanisms.
- This research supports further evaluation of dacomitinib's therapeutic efficacy and safety profile in NSCLC treatment.
