Compound 6c was a potent DPP-4 inhibitor designed and synthesized by our group. Previous study indicated that compound 6c had a long terminal half time and could be administrated once a week. In vitro and in vivo biological evaluation showed good antidiabetic activity. For further development, more pharmacokinetic behavior needed to be investigated. In this paper, a rapid and sensitive method for the quantification of compound 6c by UPLC-MS/MS was established and validated. Chromatographic separation was achieved by an Exsil Mono C18 (50 mm * 2 mm, 3 μm) column with gradient elution. Sitagliptin was selected as the internal standard. Multiple reaction monitoring (MRM) was employed in positive mode for the detection of compound 6c and the internal standard. The linear range was 1-1000 ng/mL and the intra-day and inter-day precision and accuracy for compound 6c were within 15%. The recoveries of quality control samples with low, medium and high concentrations were 106.34%, 102.54% and 103.94%, and the corrected matrix effects were 86.47%, 90.11% and 101.66% respectively. The samples were stable under different conditions. The validated method was then successfully applied to pharmacokinetic studies in rats after an oral administration of compound 6c. Results showed that there were significant differences in pharmacokinetic parameters between male and female rats. The elimination half-life (t1/2) of male rats was about 30 hours and that of female rats was about 55 hours. In the dose range of 1.75-7 mg/kg, compound 6c probably exhibited linear pharmacokinetics in rats. Compound 6c could be detected in a variety of tissues, with the highest content in the lung, suggesting the possible effect on lung cancer or other respiratory diseases. The cumulative excretion of compound 6c in urine and feces were extremely low. The comprehensive pharmacokinetics, distribution and excretion results may play an important role in the further development of compound 6c.
Keywords: DPP-4 inhibitor; Excretion; Pharmacokinetics; Tissue distribution; UPLC-MS/MS.
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