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Drug Metabolism and Disposition Fast Forward
First published on September 19, 2007; DOI: 10.1124/dmd.107.016055

0090-9556/07/3512-2232-2241$20.00
DMD 35:2232-2241, 2007

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In Vitro Metabolism of the Analgesic Bicifadine in the Mouse, Rat, Monkey, and HumanFormula

David A. Erickson, Stacy Hollfelder, Justin Tenge, Mark Gohdes, Jeffrey J. Burkhardt, and Philip A. Krieter

Department of Drug Metabolism, Covance Laboratories Inc., Madison, Wisconsin (D.A.E., S.H., J.T., M.G., J.B.); and DOV Pharmaceutical Inc., Somerset, NJ (P.A.K.)

The in vitro metabolism of [14C]bicifadine by hepatic microsomes and hepatocytes from mouse, rat, monkey, and human was compared using radiometric high-performance liquid chromatography and liquid chromatography/tandem mass spectrometry. Two main metabolic pathways were identified in all four species. One pathway was an NADPH-dependent pathway in which the methyl group was oxidized to form a hydroxymethyl metabolite (M2). Its formation was inhibited in human microsomes only by quinidine, a CYP2D6 inhibitor. In incubations with individual cDNA-expressed human cytochromes P450, M2 was formed only by CYP2D6 and CYP1A2, with CYP2D6 activity 6-fold greater than that of CYP1A2. M2 was oxidized further to the carboxylic acid metabolite (M3) by hepatocytes from all four species. The second major metabolic pathway was an NADPH-independent oxidation at the C2 position of the pyrrolidine ring, forming a lactam metabolite (M12). This reaction was almost completely inhibited in human hepatic microsomes and mitochondria by the monoamine oxidase (MAO)-B-specific inhibitor selegiline. Clorgyline, a specific inhibitor of MAO-A, was less effective in inhibiting M12 formation. Other metabolic pathways of variable significance among the four species included the formation of carbamoyl-O-glucuronide, hydroxymethyl lactam, and carboxyl lactam. Overall, the data indicate that the primary enzymes responsible for the primary metabolism of bicifadine in humans are MAO-B and CYP2D6.

Address correspondence to: Dr. Philip A. Krieter, DOV Pharmaceutical, Inc., 150 Pierce St., Somerset, NJ 08873. E-mail: pkrieter{at}dovpharm.com




This article has been cited by other articles:


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 Drug Metab. Dispos.Home page
P. A. Krieter, M. Gohdes, T. J. Musick, F. P. Duncanson, and W. E. Bridson
Pharmacokinetics, Disposition, and Metabolism of Bicifadine in Humans
Drug Metab. Dispos., February 1, 2008; 36(2): 252 - 259.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
T. J. Musick, M. Gohdes, A. Duffy, D. A. Erickson, and P. A. Krieter
Pharmacokinetics, Disposition, and Metabolism of Bicifadine in the Mouse, Rat, and Monkey
Drug Metab. Dispos., February 1, 2008; 36(2): 241 - 251.
[Abstract] [Full Text] [PDF]


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