title: Plasma levels of rotigotine and the reversal of motor deficits in MPTP-treated primates.
abstract: Rotigotine is a nonergolinic dopamine D3/D2/D1-receptor agonist used clinically for the treatment of Parkinson's disease. This study aimed to determine the relationship between peak antiparkinsonian activity and drug plasma levels after administration of rotigotine to 1-methyl-4-phenyl-1,2,3,6-tetrahydropytidine-treated primates. Using single subcutaneous injections of rotigotine and blood sampling at two subsequent time points, the relationship between improvement in motor activity and plasma rotigotine level was evaluated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropytidine-treated common marmosets. Rotigotine (0.01875-0.3 mg/kg subcutaneously) produced an increase in locomotor activity even at the lowest dose tested. Total increase in motor activity and duration of drug effect were dose related. Motor disability was similarly improved by rotigotine in a dose-dependent manner. At the highest doses, hyperactivity and stereotypy were observed. Plasma concentrations of rotigotine were linearly related to dose over dosage range employed, but not to behavioral response. Results show that pulsatile administration of rotigotine effectively normalizes motor activity in 1-methyl-4-phenyl-1,2,3,6-tetrahydropytidine-treated marmosets. Although dose and plasma concentrations of rotigotine are closely related, drug effects in the brain measured as locomotion and improvement of disability dissociate from plasma levels. Plasma levels corresponding to the optimal dose range (0.01875-0.075 mg/kg) will guide a continuous administration regimen of rotigotine in a subsequent study using the same experimental model of Parkinson's disease.
authors.affiliation: aNeurodegenerative Disease Research Centre, School of Health and Biomedical Sciences, King's College London, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Rose
authors.forename: Dieter K A
authors.initials: DK
authors.lastname: Scheller
authors.forename: Alexander
authors.initials: A
authors.lastname: Breidenbach
authors.forename: Lance
authors.initials: L
authors.lastname: Smith
authors.forename: Michael
authors.initials: M
authors.lastname: Jackson
authors.forename: Kim
authors.initials: K
authors.lastname: Stockwell
authors.forename: Peter
authors.initials: P
authors.lastname: Jenner
mesh_terms: D000818:Animals; D002144:Callithrix; D004305:Dose-Response Relationship, Drug; D005260:Female; D006948:Hyperkinesis / Q000139:chemically induced / Q000523:psychology; D007279:Injections, Subcutaneous; D020267:MPTP Poisoning / Q000188:drug therapy* / Q000523:psychology; D009043:Motor Activity / Q000187:drug effects; D013239:Stereotyped Behavior / Q000187:drug effects; D013764:Tetrahydronaphthalenes / Q000097:blood* / Q000627:therapeutic use*; D013876:Thiophenes / Q000097:blood* / Q000627:therapeutic use*
chemical_list: D013764:Tetrahydronaphthalenes; D013876:Thiophenes; C047508:rotigotine