Studies on the Metabolic Fate of a Novel Orally Active Nonpeptide Endothelin Antagonist TA-0201: Metabolism and First pass Metabolism of TA-0201 in Rats
1998 Volume 13 Issue 6 Pages 546-556
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1998 Volume 13 Issue 6 Pages 546-556
TA-0201 is a novel orally active non-peptide antagonist for endothelin receptors. Metabolism and pharmacokinetics of TA-0201 were investigated in rat. Animal and human liver microsomes were used to investigate the metabolism of TA-0201 in vitro.
1. The structures of main metabolites were identified to be carboxylic acid form (CA) and diol form (Diol) by comparison with authentic sample using LC/MS/MS. Intrinsic clearances (CLint) for the conversion of TA-0201 to CA by liver microsomes of different species were in the following order of monkey>>dog>human>rat. The isozyme catalyzing the metabolic reaction of TA-0201 to CA and Diol was determined. It was supposed that CYP3A family contributed mainly to these metabolic reactions.
2. Pharmacokinetic studies of TA-0201 in the rat were investigated, the bioavailability (BA) in male rats was calculated as 60%. More than 90% of TA-0201 was disappeared from the body by metabolism. Hepatic and gastro intestinal extractions were 0.21 and 0.11, respectively. Contributions of the two organs in the first-pass extraction of TA-0201 after oral administration were of the same degree.
