Mechanism of action<unk>  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<unk>  inhibits COMT activity. Thus,<unk>  improves the bioavailability and reduces the clearance of levodopa and subsequently dopamine from the CNS. 3-O-Methylation of levodopa (3-hydroxy-L-tyrosine) via COMT activity The strength of the binding affinity of<unk> , 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<unk>  (Vmax = 58.4 pmol/min·mg). Pharmacokinetics<unk>  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. 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<unk>  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.<unk>  and its metabolites. The reduction to the amine and subsequent N-acetylation is putative. 99% of<unk>  is in monoanionic form in the body because the physiological pH is 7.4.<unk>  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<unk> , 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.
Tolcapone
Dimethazan
Acolbifene
Lorcaserin
Pretomanid
Quinagolide
Olsalazine
Entropion