Capmatinib, a recently approved tyrosine kinase inhibitor, is used for the treatment of non-small cell lung cancer. We describe two new HPLC methods for capmatinib quantification in vivo and in vitro. HPLC with a fluorescence detection method was used to quantify capmatinib in plasma for the first time. The method was successfully applied in a pharmacokinetic study following a 10 mg/kg oral dose of capmatinib given to rats. The chromatographic separation was performed using a Eurospher II 100-3 C18H (50 × 4 mm, 3 µm) column and a mobile phase containing 10 mM of ammonium acetate buffer (pH 5.5): acetonitrile (70:30, v/v), at a flow rate of 2.0 mL min–1. The study also describes the use of HPLC-PDA for the first time for the determination of capmatinib in human liver microsomes and describes its application to study its metabolic stability in vitro. Our results were in agreement with those reported using LC-MS/MS, demonstrating the reliability of the method. The study utilized a Gemini-NX C18 column and a mobile phase containing methanol: 20 mM ammonium formate buffer pH 3.5 (53:47, v/v), delivered at a flow rate of 1.1 mL min−1. These methods are suitable for supporting pharmacokinetic studies, particularly in bioanalytical labs lacking LC-MS/MS capabilities.
Background: Erlotinib is a selective epidermal growth factor receptor inhibitor that is used for the treatment of non‐small cell lung cancer and pancreatic cancer. Its metabolism is mainly mediated by cytochrome P450 3A (CYP 3A). Resveratrol, a natural compound found in many plants and supplements, is known to inhibit CYP3A enzyme, therefore, it may act as an inhibitor for the metabolism of erlotinib. Objective: Development of a rapid high performance liquid chromatography with photodiode array detection (HPLC‐PDA) method for the quantification of erlotinib in liver microsomes and cancer cells and its application to study resveratrol effect on metabolism and cellular uptake of erlotinib. Methods: HPLC‐PDA was used to develop an efficient bioanalytical method with a 2.5‐min runtime preceded by a simple protein precipitation step. The method was validated according to the European Medicines Agency guidelines. Erlotinib metabolic stability and resveratrol effect on erlotinib metabolite formation were evaluated in rat liver microsomes. Furthermore, the method was used to measure the intracellular concentrations of erlotinib in cancer colorectal cells and investigating resveratrol effect on the cellular uptake of erlotinib. Results: A rapid HPLC‐PDA method was developed and validated for the first time to address potential drug interaction of erlotinib with resveratrol. Resveratrol was a strong inhibitor of erlotinib metabolism in vitro with IC50 = 4.03 μM. Resveratrol, however, had no effect on erlotinib cellular uptake after 1 h incubation in human colorectal cancer cells. Conclusion: The study suggests that resveratrol may produce a potential herb–drug interaction with erlotinib at the metabolism level and should be investigated in patients in the clinic.
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