Development and validation of an analytical method for regorafenib and its metabolites in mouse plasma
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 and precise quantitation of regorafenib and its main metabolites in mouse plasma, and is suitable for evaluation of transporter-dependent pharmacokinetic properties of these agents in vivo.
|Persistent URL||dx.doi.org/10.1016/j.jchromb.2018.05.005, hdl.handle.net/1765/112949|
|Journal||Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences|
Fu, Q. (Qiang), Chen, M. (Mingqing), Hu, S, McElroy, C.A. (Craig A.), Mathijssen, A.H.J, Sparreboom, A, & Baker, S.D. (2018). 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, 1090, 43–51. doi:10.1016/j.jchromb.2018.05.005