Contribution of Human Liver and Intestinal Carboxylesterases to the Hydrolysis of Selexipag In Vitro.

In liver microsomes, selexipag (NS-304; ACT-293987) mainly undergoes hydrolytic removal of the sulfonamide moiety by carboxylesterase 1 (CES1) to yield the pharmacologically active metabolite MRE-269 (ACT-333679). However, it is not known how much CES in the liver and intestine contributes to the hydrolysis of selexipag or how selexipag is metabolized in the intestine, including by hydrolysis. To obtain a better understanding of selexipag metabolism in humans, we determined the percentage contribution of CES1 and carboxylesterase 2 (CES2) to the hydrolysis of selexipag and 7 of its analogs with different sulfonamide moieties and evaluated its nonhydrolytic metabolism in human liver microsomes and human intestinal microsomes (HIMS). For selexipag, the percentage contributions of CES1 and CES2 in human liver microsomes were 77.0% and 9.99%, respectively, while the percentage contribution of CES2 in HIMS was 100%. In HIMS, the rate of hydrolysis of selexipag was the lowest among the compounds tested, and no difference between the presence and absence of nicotinamide adenine dinucleotide phosphate was noted. We infer from these results that selexipag is likely to be hydrolyzed by CES2 as well as CES1, and only selexipag itself and the MRE-269 produced by hydrolysis in the intestine would be absorbed after oral administration.