Development and validation of an analytical method for regorafenib and its metabolites in mouse plasma

Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
Qiang FuSharyn D Baker

Abstract

An analytical method was developed for measuring the effect of OATP1B2 deficiency on plasma levels of the kinase inhibitor regorafenib and its metabolites regorafenib-N-oxide, N-desmethyl-regorafenib-N-oxide, and regorafenib-N-β-glucuronide (RG) in mice. Compounds were separated by liquid chromatography and monitored by a triple quadrupole mass spectrometer in the selected reaction monitoring mode after positive electrospray ionization. All calibration curves were linear in the selected concentration range (R2 ≥ 0.99). The lower limit of quantification was 5 ng/mL for the four analytes. Within-day precisions, between-day precisions, and accuracies were 2.59-6.82%, 3.97-11.3%, and 94.5-111%, respectively. The identification and structure elucidation of RG, isolated from human urine, was performed by NMR. Compared with wild-type mice given regorafenib (10 mg/kg), deficiency of the drug transporter OATP1B2 in vivo had minimal effects on plasma levels of parent drug and the metabolite regorafenib-N-oxide, and N-desmethyl-regorafenib-N-oxide. However, the area under the curve and peak levels of RG were increased by 5.6-fold and 5.1-fold, respectively, in OATP1B2-knockout mice. In conclusion, our analytical method allowed accurate an...Continue Reading

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