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

Abstract

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 reaction monitoring 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 1–2,000 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 to be 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.