Metabolism of Opicapone, a Novel COMT Inhibitor, in the Rat: Characterization of In Vitro Sulfation

Abstract

In this study, opicapone, a novel catechol‐O‐methyltransferase (COMT) inhibitor, metabolism was evaluated in the rat and the sulfotransferases (SULTs) responsible for opicapone sulfation were characterized. Opicapone 3‐O‐sulfate was present in monkey, dog, rat and human liver cellular fractions and represented the major metabolite in the rat. Regarding human kidney, liver and small intestine cellular fractions, the later displayed the highest activity towards opicapone sulfation. A systematic analysis of seven recombinant human SULTs, showed that SULT1A1*1 and SULT1A1*2 exhibited the highest catalytic activity for opicapone sulfation. The kinetic analysis of opicapone sulfation revealed that the affinity for the conjugation of opicapone by intestinal S9 fraction was 20‐fold higher than that for the liver S9 fraction. Similar apparent Km values were obtained for SULT1A1 and human liver S9. Opicapone sulfation by human S9 fractions and SULT1A1 isoform was inhibited in a concentration manner by quercetin and 2,6‐dichloro‐4‐nitrophenol, highly selective inhibitors of SULT1A1. Dopamine, the major endogenous substrate of SULT1A3, also inhibited opicapone sulfation, but acetaminophen had no effect. The enhanced catalytic activity for opicapone sulfation and the high level of expression of SULT1A1 in liver together with the similar Km values obtained for SULT1A1 and for human liver S9 fraction, suggest that SULT1A1 may play a major role in opicapone sulfation, though other SULTs, such as SULT1A3, may also be involved in opicapone sulfation, namely at the intestinal level.