Effect of liver impairment on the pharmacokinetics of tolcapone and its metabolites.
OBJECTIVE
To assess the effect of liver impairment on the pharmacokinetics of tolcapone and to derive appropriate dose recommendations for patients with this disease who are undergoing treatment for Parkinson's disease.


METHODS
In an open, two-way crossover study, 16 patients with moderate liver disease (eight with cirrhotic and eight with noncirrhotic liver disease) and eight healthy subjects received an oral dose of 200 mg tolcapone and an intravenous dose of 50 mg tolcapone on separate occasions. The concentrations of total and unbound tolcapone and its three major metabolites (tolcapone glucuronide, carboxylic acid, and 3-O-methyl metabolite) were assessed in plasma and urine.


RESULTS
On the basis of total drug concentration, the differences in tolcapone pharmacokinetics between 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 concentration of the pharmacologically inactive glucuronide metabolite was increased among patients with cirrhosis.


CONCLUSIONS
Half of the recommended dosage of tolcapone should be administered to patients with cirrhosis of the liver to maintain the target steady-state concentration of unbound drug and to avoid accumulation of tolcapone glucuronide. Our data did not indicate a requirement for dosage adjustment in the presence of moderate chronic hepatitis.
Jorga
K M
KM
Department of Research and Development, F. Hoffmann-La Roche Ltd., Basel, Switzerland. karin.jorga@roche.com
Kroodsma
J M
JM
Fotteler
B
B
Heizmann
P
P
Meyer
J
J
Rasch
M C
MC
van Hattum
J
J
D000328:Adult; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001577:Benzophenones / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008107:Liver Diseases / Q000097:blood*; D008297:Male; D008875:Middle Aged; D009596:Nitrophenols; D000077867:Tolcapone
D000978:Antiparkinson Agents; D001577:Benzophenones; D004791:Enzyme Inhibitors; D009596:Nitrophenols; D000077867:Tolcapone