Metabolism and excretion of tolcapone, a novel inhibitor of catechol‐O‐methyltransferase

Abstract

Aims To investigate the rate of excretion and routes of metabolism of tolcapone, a novel inhibitor of catechol-O-methyltransferase (COMT). Methods Six healthy male volunteers were given 200 mg [14 C]-tolcapone (approximately 50 mCi) orally. To assess excretion balance and to identify metabolites, urine and faeces were collected before administration and until radioactivity fell below 75 d min −1 ml −1 (urine) and 100 d min −1 mg −1 (faeces). Blood samples were collected frequently before and after administration to determine plasma radioactivity, to identify tolcapone metabolites and to measure plasma tolcapone and its methylated derivative 3-O-methyltolcapone (3-OMT).Results The mean proportion of the dose excreted in urine was 57.3% and in faeces 40.5%. Excretion was almost complete (more than 95%) in all participants after 9 days. The major early metabolite present in plasma was the 3-O-b,d-glucuronide conjugate, which was detectable within 2 h after dosing. The major late metabolite in plasma was 3-OMT. The 3-O-b,d-glucuronide was also the most abundant metabolite in urine and faeces, accounting for 27% and 33%, respectively, of the total radioactivity excreted by these routes and for 26% of the original dose. Reduction of the nitro moiety yields an amine derivative, detected in both urine and faeces, with subsequent modifications, such as acetylation of the amine group and conjugation with glucuronic acid or sulphate, or both. Oxidative reactions due to cytochrome P450 enzymes are of small significance, as is 3-O-methylation by COMT. Conclusions Tolcapone is almost completely metabolized and excreted in urine and faeces (only 0.5% of tolcapone was excreted unchanged); glucuronidation is the most important route of metabolism. The relatively long duration of excretion is caused by the long half-life of 3-OMT.

Rapid screening and characterization of drug metabolites using a new quadrupole–linear ion trap mass spectrometer

“…Tolcapone is a catechol-O-methyl transferase inhibitor. 12 For tolcapone, negative ionspray works best, but a weaker signal can also be observed in the positive ion mode. 13 The most intense peak at retention time 5.8 min in the LC/MS analysis using ionspray in negative mode corresponds to a metabolite with a molecular mass of 447 Da.…”

Tolcapone Improves Cognition and Cortical Information Processing in Normal Human Subjects

“…Prior studies have shown that plasma levels peak about 1.5-2.0 h after administration of tolcapone and maximum inhibition of COMT activity in red blood cells is achieved between 1 and 4 h following administration of the drug (Jorga et al, 1999;Jorga, 1998;Mannisto and Kaakkola, 1999). Therefore, neuropsychological testing (NPT) and fMRI were performed 2 h after the dose of tolcapone on day 7 and the neuropsychological battery was completed in 75-80 min for the NPT and 60-75 min for the fMRI.…”

Human Metabolism of Nebicapone (BIA 3-202), a Novel Catechol-O-Methyltransferase Inhibitor: Characterization of in Vitro Glucuronidation

“…Major metabolites of tolcapone in human plasma are the 3-O-␤-glucuronic acid (ϳ18.6%) and the 3-O-methyl conjugate (ϳ2.1%). In urine, the 3-O-␤-glucuronic conjugates of tolcapone (ϳ13%) and its derivative N-acetyl amino (ϳ5.7%) are the predominant metabolites found (Jorga et al, 1999). Regarding entacapone, the only metabolite described in human plasma is the Zisomer (ϳ5%) (Wikberg et al, 1993;Keranen et al, 1994); however, in human urine, besides the Z-isomer (ϳ25%), the 3-O-␤-glucuronic acid derivative (ϳ70%) is the prevalent metabolite (Wikberg et al, 1993).…”

“…As an alternative to molecular conjugation with endogenous species like glucuronidation, sulfation, methylation, glutathione conjugation, and acetylation (phase II drug metabolism reactions), these drugs could undergo oxidation, reduction, and hydroxylation (phase I drug metabolism reactions); however, such phase I metabolites are minor (Wikberg et al, 1993;Jorga et al, 1999). …”