title: Pharmacokinetics, enantiomer interconversion, and metabolism of R-apomorphine in patients with idiopathic Parkinson's disease.
abstract: The pharmacokinetics and metabolism of R-apomorphine were determined in 10 patients with idiopathic Parkinson's disease after intravenous infusion of 30 micrograms.kg-1 in 15 min. Specifically, emphasis was on enantiomeric interconversion into S-apomorphine and on the formation of apocodeine and isoapocodeine, since these metabolites may interfere with the pharmacodynamics of R-apomorphine. The pharmacokinetics of R-apomorphine in plasma were determined using an enantioselective high-performance liquid chromatography assay. In most patients, the plasma concentration versus time profile was characterized by a biexponential function. The values of relevant pharmacokinetic parameters were as follows: clearance 40 +/- 15 ml.min-1.kg-1, volume of distribution at steady state 1.6 +/- 0.5 l.kg-1, and terminal half-life 41 +/- 13 min. No measurable concentrations of S-apomorphine were detected in plasma, indicating that enantiomeric interconversion does not occur in vivo. Furthermore, no measurable concentrations of the methylated metabolites apocodeine and isoapocodeine could be detected in plasma. The metabolism of apomorphine was characterized on basis of the excretion of unchanged R-apomorphine, S-apomorphine, apocodeine, isoapocodeine, and their respective sulfate and glucuronide conjugates in urine. The total excretion of unconjugated S-apomorphine, apocodeine, and isoapocodeine was less than 0.1% of the administered dose. The total excretion of unchanged apomorphine, apomorphine sulfate, and apomorphine glucuronide amounted to 0.3 +/- 0.4%, 3.8 +/- 1% and 6.0 +/- 2.2% of the administered dose, respectively. The findings of this study show that on intravenous administration, S-apomorphine and the metabolites apocodeine and isoapocodeine are unlikely to interfere with the pharmacologic actions of R-apomorphine in patients with idiopathic Parkinson's disease. Furthermore, no pharmacokinetic interaction between R-apomorphine and catechol-O-methyl transferase inhibitors is expected.
authors.affiliation: Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, University of Leiden, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: van der Geest
authors.forename: T
authors.initials: T
authors.lastname: van Laar
authors.forename: P P
authors.initials: PP
authors.lastname: Kruger
authors.forename: J M
authors.initials: JM
authors.lastname: Gubbens-Stibbe
authors.forename: H E
authors.initials: HE
authors.lastname: Boddé
authors.forename: R A
authors.initials: RA
authors.lastname: Roos
authors.forename: M
authors.initials: M
authors.lastname: Danhof
mesh_terms: D000328:Adult; D000368:Aged; D000978:Antiparkinson Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001058:Apomorphine / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D018491:Dopamine Agonists / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004409:Dyskinesia, Drug-Induced; D005260:Female; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism*; D011485:Protein Binding; D011930:Reaction Time / Q000187:drug effects; D013237:Stereoisomerism
chemical_list: D000978:Antiparkinson Agents; D018491:Dopamine Agonists; D001058:Apomorphine