Comparative toxicological study on the hepatic safety of entacapone and tolcapone in the rat.
Entacapone and tolcapone are novel COMT (catechol-O-methyltransferase) inhibitors indicated for the adjunctive treatment of Parkinson's disease (PD) in combination with levodopa. The marketing authorisation of tolcapone was suspended in the European Union (EU) in 1998 mainly due to severe abnormal hepatic reactions. This fact raised concern about the safety of COMT inhibitors in the treatment of parkinsonian patients. In order to investigate whether these COMT inhibitors exhibit different effects on the liver comparative toxicological studies were performed in the rat. Short term toxicological studies in rats at high oral doses of entacapone and tolcapone (200, 400 or 600mg/kg daily) were carried out. Tolcapone (400 mg/kg/day or 600 mg/kg/day) increased mortality after only one week treatment and induced signs of toxicity such as a rise in body temperature, stimulation of respiration and rapid onset of rigor mortis after death. Entacapone did not show any adverse effects at the tested dose levels. In the histopathological examination liver cell necrosis was observed in the tolcapone (400 and 600mg/kg/day) treated rats, but it revealed no treatment related signs of toxicity in entacapone-treated rats. We conclude that the toxicological profile of the two COMT inhibitors, entacapone and tolcapone, differ from each other, tolcapone--unlike entacapone--showed hepatotoxicity.
Orion Corporation, Orion Pharma, Espoo, Finland. kristiina.haasio@orionpharma.com
K
K
Haasio
L
L
Sopanen
L
L
Vaalavirta
I B
IB
Lindén
E H
EH
Heinonen
D000818:Animals; D000978:Antiparkinson Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D001577:Benzophenones / Q000493:pharmacokinetics / Q000633:toxicity*; D001831:Body Temperature / Q000187:drug effects / Q000502:physiology; D002396:Catechols / Q000493:pharmacokinetics / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004798:Enzymes / Q000097:blood / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D009570:Nitriles; D009596:Nitrophenols; D010300:Parkinson Disease / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015996:Survival Rate; D000077867:Tolcapone
D000978:Antiparkinson Agents; D001577:Benzophenones; D002396:Catechols; D004798:Enzymes; D009570:Nitriles; D009596:Nitrophenols; C071192:entacapone; D000077867:Tolcapone