Preclinical pharmacokinetics and metabolism study of SCO-267, a GPR40 full agonist, in beagle dogs using ultra-high performance liquid chromatography coupled to tandem mass spectrometry

SCO-267 is a GPR40 full agonist that has been developed for the treatment of diabetes. To support its preclinical and clinical development, in this study, we developed an ultra-high performance liquid chromatography tandem mass spectrometric method for the determination of SCO-267 in dog plasma using cabozantinib as internal standard (IS). The chromatographic separation was obtained on a Waters acquity BEH C₁₈ column (50×2.1 mm, I.D., 1.7 μm) and the detection was performed using Thermo TSQ triple quadrupole mass spectrometer with multiple reactions monitoring (MRM) positive mode at m/z 615.3>230.1 for SCO-267 and m/z 502.5>323.3 for IS. The method was validated over the concentration range of 1-2000 ng/mL with the lower limit of quantification of 1 ng/mL. The selectivity, linearity, precision and accuracy over this range were acceptable. The extraction recovery was more than 88.73% and no matrix effect was observed. SCO-267 was demonstrated stable during the storage and processing period. The new method was successfully applied to the pharmacokinetic study in beagle dogs following a single oral and intravenous administration. The oral bioavailability was 64.34%. In addition, the metabolites from dog liver microsomal incubation and plasma collected after an oral administration were identified by a UHPLC-HRMS method. The biotransformation pathways of SCO-267 involved oxygenation, O-demethylation, N-dealkylation and acyl glucuronidation.