Evaluation of species differences in the metabolism of the selective Na_V1.7 inhibitor DS-1971a, a mixed substrate of cytochrome P450 and aldehyde oxidase

Abstract

1. Nonclinical metabolite profiling of DS-1971a, a potent selective Na_V1.7 inhibitor, was performed to predict human metabolites.

2. After the oral administration of radiolabelled DS-1971a, the predominant metabolite in mouse plasma was M4, a monoxide at the pyrimidine ring, while the major metabolites with the first and second highest exposure in monkey plasma were M2, a monoxide at the cyclohexane ring, and M11, a demethylated pyrazole metabolite.

3. Incubation studies with liver cytosolic and microsomal fractions in the absence or presence of NADPH indicated that the metabolising enzyme responsible for M4 formation was aldehyde oxidase (AO), while cytochrome P450s (P450s) were responsible for M2 and M11 formation. These results suggest that DS-1971a is a substrate for both AO and P450.

4. When DS-1971a was incubated with liver S9 fractions and NADPH, the most abundant metabolites were M4 in mice, and M2 and M11 in monkeys, indicating that the results of in vitro incubation studies could provide information reflecting the in vivo plasma metabolite profiles in mice and monkeys. The results obtained from the incubation with the human liver S9 fraction and NADPH suggested that a major circulating metabolite in humans is M1, a regioisomer of M2.

Keywords:

• Aldehyde oxidase (AO)
• cytochrome P450 (P450)
• mixed substrate of non-P450 and P450 enzymes
• species difference in metabolism in vitro-in vivo correlation (IVIVC)
• human metabolite prediction

Acknowledgments

The authors thank Sekisui Medical Co., Ltd., for performing the mass balance study in monkeys.

Disclosure statement

The authors are employees of Daiichi Sankyo Co., Ltd., or University of Shizuoka.