title: The COMT inhibitor, entacapone, reduces levodopa-induced elevations in plasma homocysteine in healthy adult rats.
abstract: Levodopa treatment has been shown to increase plasma homocysteine levels in Parkinson's disease (PD) patients and this may lead to an increased risk for coronary arterial diseases. Levodopa is metabolised via O-methylation by catechol-O-methyltransferase (COMT) using S-adenosyl-L-methionine (SAM) as the methyl donor, this leading to the subsequent formation of homocysteine. In this study, the effects of the COMT inhibitor, entacapone, on levodopa-induced hyperhomocysteinaemia were studied in rats. Using a single dose acute treatment paradigm, entacapone (10 or 30 mg/kg) prevented the levodopa (30 or 100 mg/kg) induced rise in plasma homocysteine levels in a dose-dependent manner. Five-day sub-chronic treatment with levodopa (3 x 100 mg/kg per day) resulted in a marked rise in plasma homocysteine levels when measured 2 hours post-treatment on Day 5. These levels fell but remained greater than baseline at 8 hours post-treatment on Day 5. Consistent with findings in the acute treatment test paradigm, the co-administration of entacapone (30 mg/kg) significantly (p<0.001) reduced levodopa-induced hyperhomocysteinaemia for up to 2 hours post-treatment on Day 5 of the sub-chronic study. These results suggest that entacapone may reduce levodopa-induced hyperhomocysteinaemia in PD patients.
authors.affiliation: Orion Pharma, Espoo, Finland. erkki.nissinen@orionpharma.com
authors.forename: E
authors.initials: E
authors.lastname: Nissinen
authors.forename: H
authors.initials: H
authors.lastname: Nissinen
authors.forename: H
authors.initials: H
authors.lastname: Larjonmaa
authors.forename: A
authors.initials: A
authors.lastname: Väänänen
authors.forename: T
authors.initials: T
authors.lastname: Helkamaa
authors.forename: I
authors.initials: I
authors.lastname: Reenilä
authors.forename: P
authors.initials: P
authors.lastname: Rauhala
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006710:Homocysteine / Q000097:blood*; D020138:Hyperhomocysteinemia / Q000139:chemically induced / Q000188:drug therapy*; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D009570:Nitriles; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000978:Antiparkinson Agents; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols; D004791:Enzyme Inhibitors; D009570:Nitriles; D006710:Homocysteine; D007980:Levodopa; C071192:entacapone