The disposition of the tolcapone 3-O-methylated metabolite is affected by the route of administration in rats.
Catechol-O-methyltransferase (COMT) catalyses the transfer of the methyl group from S-adenyl-L-methionine (SAM) to one of the hydroxy groups of a catechol, usually the hydroxy group in position 3. COMT is present mainly in a soluble form (S-COMT) in the cytosol, but a small fraction is bound to cell membranes (MB-COMT). MB-COMT has higher affinity for the catechol substrate than does S-COMT by a factor of > 10, and high MB-COMT activity is observed in the intestinal muscle layer. The present study investigates the effect of the administration route on the disposition of the tolcapone 3-O-methylated metabolite following intravenous and oral tolcapone administration in rats. Tolcapone is a substrate for COMT although the 3-O-methylated metabolite produced has no pharmacological actions. The 3-O-methylated metabolite was eliminated very slowly following oral administration of tolcapone, and its concentration approached a plateau level, which was in contrast to the situation following intravenous administration of tolcapone. It is thought that the oral dose of tolcapone receives a high exposure to MB-COMT in the intestinal muscle layer during its absorption, and tolcapone seems to form a complex with MB-COMT having a high affinity constant (i.e. a very low Ki). The fraction of the intravenous dose of tolcapone metabolized to the 3-O-methylated metabolite at 10 mg kg-1 was 2.6%, whereas those of the oral doses, which were corrected by the bioavailability, were 5.4% for 20 mg kg-1 and 2.7% for 40 mg kg-1.
Funaki
T
T
Nippon Roche Research Center, Kanagawa, Japan.
Onodera
H
H
Ushiyama
N
N
Tsukamoto
Y
Y
Tagami
C
C
Fukazawa
H
H
Kuruma
I
I
D000284:Administration, Oral; D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D001577:Benzophenones / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001682:Biological Availability; D065098:Catechol O-Methyltransferase Inhibitors; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D007275:Injections, Intravenous; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D008745:Methylation; D009130:Muscle, Smooth / Q000378:metabolism; D009596:Nitrophenols; D051381:Rats; D017207:Rats, Sprague-Dawley; D012044:Regression Analysis; D013379:Substrate Specificity; D000077867:Tolcapone
D000978:Antiparkinson Agents; D001577:Benzophenones; D065098:Catechol O-Methyltransferase Inhibitors; D009596:Nitrophenols; D000077867:Tolcapone