The main inactivation step is glucuronidation; other processes are methylation by COMT, hydroxylation by CYP3A4 and CYP2A6 with subsequent oxidation to a carboxylic acid, and possibly a minor path with reduction to an amine with subsequent acetylation.The half-life of tolcapone is two to three hours, the volume of distribution (Vd) being 0.3 L/kg (21 L in an average 70 kg person). 60% of the metabolites are excreted via the urine and 40% via the feces. Only 0.5% of the drug are excreted in unchanged form via the urine. 99% of tolcapone is in monoanionic form in the body because the physiological pH is 7.4. Tolcapone penetrates the blood–brain barrier much better than two other nitrocatechols, nitecapone and entacapone, because it has higher lipophilicity due to its R-substituent. Partition coefficients quantify the ability of the molecule to cross the blood–brain barrier. LogPIdce= 0.2, –1.4, –0.4 for tolcapone, nitecapone and entacopone respectively. Partition coefficients in this case were measured in 1,2-dichloroethane/H2O solution which caused molecules to be in ionized form. There is no current explanation for how these charged molecules permeate the blood–brain barrier. Chemistry
Tolcapone is an intensely yellow, odorless, bitter tasting, non-hygroscopic, crystalline compound with a relative molecular mass of 273.25 g/mol. It melts at 143 to 146 °C (289 to 295 °F), is practically insoluble in water and acids but soluble in 0.1 M aqueous sodium hydroxide solution. The pKa values are 4.5 and 10.6 for the two phenyl groups; and the maximum absorption is at 268 nm (in 0.1 M hydrochloric acid / ethanol).
Combination with non-selective MAO inhibitors might be dangerous.Due to its affinity to the liver enzyme CYP2C9, interactions with drugs being metabolised by this enzyme are also possible, but unlikely. No interaction with tolbutamide, a 2C9 substrate, was observed in studies. Pharmacology
Mechanism of action
Tolcapone selectively and reversibly binds to the catalytic site of COMT in both the periphery and the central nervous system (CNS) with greater affinity than any of the three catecholamines, including levodopa. It thereby prevents the 3-O-methylation of levodopa by COMT in the periphery, which produces 3-O-methyldopa, a major metabolite that competes with levodopa to cross the blood–brain barrier. More of the levodopa that is administered reaches the CNS. Additionally, levodopa that has already reached the CNS, after being converted to dopamine, will not be degraded as quickly when tolcapone inhibits COMT activity. Thus, tolcapone improves the bioavailability and reduces the clearance of levodopa and subsequently dopamine from the CNS. The strength of the binding affinity of tolcapone, represented by the inhibition constant Ki (2.5 nM), can be thought of as the dissociation constant for enzyme and inhibitor complex kinetics. Maximum catalytic activity denotes the efficacy of tolcapone (Vmax = 58.4 pmol/min·mg). Pharmacokinetics
Tolcapone is quickly absorbed from the gut to about 85%. It has an absolute bioavailability of 65%, which is only slightly decreased when taken with food. The substance reaches highest blood plasma concentrations after about two hours. When in the bloodstream, it is almost completely (>99.9%) bound to plasma proteins, primarily albumin.