EFFECT OF LIVER IMPAIRMENT ON THE PHARMACOKINETICS OF TOLCAPONE AND ITS METABOLITES

Objective: To assess the effect of liver impairment on the pharmacokin etics of tolcapone and to derive appropriate dose recommendations for patients with this disease who are undergoing treatment for Parkinson' s disease. Study design: In an open, two-way crossover study, 16 patie nts with moderate liver disease (eight with cirrhotic and eight with n oncirrhotic liver disease) and eight healthy subjects received an oral dose of 200 mg tolcapone and an intravenous dose of 50 mg tolcapone o n separate occasions. The concentrations of total and unbound tolcapon e and its three major metabolites (tolcapone glucuronide, carboxylic a cid, and 3-O-methyl metabolite) were assessed in plasma and urine. Res ults: On the basis of total drug concentration, the differences in tol capone pharmacokinetics beta een the groups were small. However, lower clearance and volume of distribution of unbound drug were found among patients with cirrhosis than among control subjects. Plasma concentra tion of the pharmacologically inactive glucuronide metabolite was incr eased among patients with cirrhosis. Conclusions: Half of the recommen ded dosage of tolcapone should be administered to patients with cirrho sis of the liver to maintain the target steady-state concentration of unbound drug and to avoid accumulation of tolcapone glucuronide, Our d ata did not indicate a requirement for dosage adjustment in the presen ce of moderate chronic hepatitis.