Pharmacokinetic study of (S)-(-)-2-(N-propyl-N-(2-thienylethyl)amino)-5-hydroxytetralin infusion in cynomolgus monkeys.
A pharmacokinetic study of the dopamine D2 receptor agonist (S)-(-)-2-(N-propyl-N-(2-thienylethyl)amino)-5-hydroxytetralin+ ++-HCl (N-0923) infused in female cynomolgus monkeys over a 4-h period was carried out at International Research and Development Corporation. The purpose of this study was to estimate the elimination half-life and elucidate the dose-clearance relationship in cynomolgus monkeys with a randomized three-way crossover intravenous (iv) infusion study design. Six female cynomolgus monkeys were dosed by iv infusion for 4 h with 0.1, 0.5, and 1.0 mg/kg/h. Plasma samples were drawn during the infusion and up to 4 h post infusion. The plasma concentrations were determined by a sensitive and specific HPLC assay with electrochemical detection after solid-phase extraction at the Department of Toxicology and Bioanalysis at the University Center for Pharmacy in Groningen, The Netherlands. The plasma data were best described by a two-compartment open model. Mean elimination half-lives of 36.8, 39.6, and 52.4 min and mean clearance values of 229 +/- 35, 202 +/- 85, and 191 +/- 36 mL/min/kg were obtained for doses of 0.1, 0.5, and 1.0 mg/kg/h, respectively. The steady-state volumes of distribution were estimated as 3.89 +/- 0.816, 3.53 +/- 1.62, and 4.70 +/- 3.67 L/kg for the same doses, respectively. There were no significant differences between any of the estimated pharmacokinetic parameters for any of the infusion doses. Clearance was not dose dependent and steady-state plasma concentration appeared directly proportional to dose, suggesting linear pharmacokinetics in this dose range for monkeys.
Walters
D R
DR
Whitby Research, Richmond, VA 23261-7426.
McConnell
W R
WR
Cefali
E A
EA
D000704:Analysis of Variance; D000818:Animals; D015259:Dopamine Agents / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D007262:Infusions, Intravenous; D008252:Macaca fascicularis; D013764:Tetrahydronaphthalenes / Q000493:pharmacokinetics*; D013876:Thiophenes / Q000493:pharmacokinetics*; D014018:Tissue Distribution
D015259:Dopamine Agents; D013764:Tetrahydronaphthalenes; D013876:Thiophenes; C047508:rotigotine