METABOLITE PROFILES OF 2 [C-14] LABELED CATECHOL O-METHYLTRANSFERASE INHIBITORS, NITECAPONE AND ENTACAPONE, IN RAT AND MOUSE URINE AND RAT BILE

The metabolites of two inhibitors of catechol O-methyltransferase, nitecapone [3-(3,4-dihydroxy-5-nitrobenzylidene)2,4-pentanedione] and entacapone [(E)-2-cyano-N,N-diethyl-3-(3,4-dihydroxy-5-nitrophenyl)propenamide], excreted in urine and bile by rats and in urine by mice, were compared and quantified by using HPLC with radiochemical detection after administration of [C-14]-labelled compounds. With the exception of 3-O-methylated nitecapone, no major metabolites were found in rat bile that were not found in rat: urine. For both compounds the major biotransformations were the same in the mouse and the rat. However, a bisulfite adduct of nitecapone was found in rat urine only, and reduction of the C=C and C=O groups of the nitecapone side chain was more extensive in the mouse. After entacapone administration, the products of amide N-dealkylation were more abundant in rat urine than in mouse urine. Most of the dose was excreted in urine and bile as O-conjugates. Most abundant were the O-glucuronides, while smaller amounts of O-sulfates and O-methylated metabolites were found in both species. One non-glucuronide glycoside of entacapone was found in urine of both rats and mice.