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).
Risk factor for cardiovascular disease
AS is not an independent predictor of cardiovascular disease, as demonstrated by a prospective cohort study of 12,745 Danes aged 20-93 followed up for an average of 22 years.The presence of AS in men less than 50 years old(arcus juvenilis) in combination with an underlying condition causing hyperlipidemia has been shown to significantly increase the relative risk of mortality from cardiovascular disease and coronary artery disease. As demonstrated by a study following 6,069 Americans aged 30-69 for an average of 8.4 years.The presence of AS in men less than 50 years old(arcus juvenilis) in conjunction with xanthomas on the achilles tendon has been linked to the presence of atherosclerosis in the coronary arteries and aorta by computed tomography. See also
Limbal ring
Limbus sign
Xanthelasma


== References ==