Abstract
The dopamine agonist rotigotine was developed for the treatment of Parkinson's disease and restless legs syndrome. Disposition, metabolism, elimination, and absolute bioavailability of rotigotine were determined in six healthy male subjects by using two different forms of administration in a randomized sequence with a crossover design. Treatment A (continuous infusion) consisted of a single radiolabeled 12-h intravenous infusion of 1.2 mg of rotigotine (0.6 mg of [14C] and 0.6 mg of unlabeled rotigotine, 3.7 MBq) solution. Treatment B (transdermal application) consisted of a single 10-cm2 patch containing 4.5 mg of unlabeled rotigotine with a patch-on period of 24 h. During the 12 h-infusion, total radioactivity concentration rapidly increased within 2 h; there was a slight additional increase toward the end of infusion. Plasma concentrations of total radioactivity declined by 75% within 12 h after completion of infusion. More than 94% of the radioactivity was excreted 216 h after the start of infusion, 71% by the kidneys and 23% by feces. Renal elimination of the parent compound was <1%. Systemically absorbed rotigotine was rapidly metabolized. The major rotigotine biotransformation pathway was conjugation of the parent compound, mainly by sulfation; a second pathway was the formation of phase 1 metabolites (N-desalkylation) with subsequent conjugation. Plasma concentration-time profiles of unchanged rotigotine during and after infusion and during and after patch administration were comparable. Absolute bioavailability of transdermally applied rotigotine was 37%.
- PD, Parkinson's disease
- HPLC, high-performance liquid chromatography
- LOQ, lower limit of quantification
- Cmax, maximum plasma concentration
- AUC, area under the plasma concentration-time curve
- Tmax, time to reach maximum plasma concentration
- t1/2, terminal phase half-life
- λz, terminal rate constant
- Aer, amount excreted into urine
- Aef, amount excreted into feces
- Er,max, maximum renal excretion rate
- Ef,max, maximum fecal excretion rate
- CLren, renal clearance
- CLf, fecal clearance.
Footnotes
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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The work was supported by the Schwarz Biosciences GmbH, UCB Group.
- Received March 3, 2009.
- Accepted July 14, 2009.
- Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics
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