Abstract
The pharmacokinetics, excretion, and metabolism of milnacipran were evaluated after oral administration of a 100-mg dose of [14C]milnacipran hydrochloride to healthy male subjects. The peak plasma concentration of unchanged milnacipran (∼240 ng/ml) was attained at 3.5 h and was lower than the peak plasma concentration of radioactivity (∼679 ng Eq of milnacipran/ml) observed at 4.3 h, indicating substantial metabolism of milnacipran upon oral administration. Milnacipran has two chiral centers and is a racemic mixture of cis isomers: d-milnacipran (1S, 2R) and l-milnacipran (1R, 2S). After oral administration, the radioactivity of almost the entire dose was excreted rapidly in urine (approximately 93% of the dose). Approximately 55% of the dose was excreted in urine as unchanged milnacipran, which contained a slightly higher proportion of d-milnacipran (∼31% of the dose). In addition to the excretion of milnacipran carbamoyl O-glucuronide metabolite in urine (∼19% of the dose), predominantly as the l-milnacipran carbamoyl O-glucuronide metabolite (∼17% of the dose), approximately 8% of the dose was excreted in urine as the N-desethyl milnacipran metabolite. No additional metabolites of significant quantity were excreted in urine. Similar plasma concentrations of milnacipran and the l-milnacipran carbamoyl O-glucuronide metabolite were observed after dosing, and the maximum plasma concentration of l-milnacipran carbamoyl O-glucuronide metabolite at 4 h after dosing was 234 ng Eq of milnacipran/ml. Lower plasma concentrations (<25 ng Eq of milnacipran/ml) of N-desethyl milnacipran and d-milnacipran carbamoyl O-glucuronide metabolites were observed.
Footnotes
This work was supported by Forest Research Institute. Medical writing and editorial assistance was also supported by Forest Research Institute.
The clinical phase of this study was conducted by Quintiles Inc. (Overland Park, KS). The authors confirmed that the article is an accurate representation of the study results.
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
ABBREVIATIONS:
- UDPGA
- UDP-glucuronic acid
- LC
- liquid chromatography
- MS/MS
- tandem mass spectrometry
- HPLC
- high-performance liquid chromatography
- SRM
- selected reaction monitoring
- LSC
- liquid scintillation counting
- HRMS
- high-resolution mass spectrometry
- AUC
- area under the curve
- dpm
- disintegrations per minute.
- Received February 15, 2012.
- Accepted May 31, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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