Abstract
Bicifadine [DOV 220,075; (±)-1-(4-methylphenyl)-3-azabicyclo[3.1.0]-hexane HCl)] is a non-narcotic analgesic that is effective in animal models of acute and chronic pain. In this study, the pharmacokinetics, disposition, and metabolism of bicifadine were determined in male and female mice, rats, and cynomolgus monkeys following single oral and i.v. doses. [14C]Bicifadine was well absorbed in all three species. The oral bioavailability of bicifadine in mice and rats was 50 to 63% and 79 to 85%, respectively, and slightly lower in monkeys (33–42%). Based on the values of the area under the concentration-time curves, unchanged bicifadine comprised 7 to 12% of the plasma radioactivity after the oral dose and 14 to 26% after the i.v. dose in all three species. The major plasma metabolites were the lactam (M12), the lactam acid (M9), and the acid (M3) plus its glucuronide conjugate. At 0.5 h after the oral dose to rats, 63 to 64% of the radioactivity in the rat brain was bicifadine, and the remainder was the lactam. Most of the radioactivity after oral and i.v. dosing to the three species was recovered in the urine. The lactam acid was the major urinary metabolite in all species; bicifadine and the lactam were either not detected or were minor components in urine. Fecal radioactivity was due to the acid and lactam acid in the three species. Rat bile contained mainly the lactam acid and the acid plus its acyl glucuronide. Plasma protein binding of [14C]bicifadine was moderate in the mouse (80–86%) and higher in the rat and monkey (95–97%). In summary, bicifadine was well absorbed, extensively metabolized, and excreted via the urine and feces as metabolites.
Footnotes
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.107.017863.
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ABBREVIATIONS: DOV 220,075, (±)-1-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane HCl (bicifadine); MAO, monoamine oxidase; BDC, bile duct-cannulated; LSC, liquid scintillation chromatography; DOV 255,828, 5-(4-methylphenyl)-3-azabicyclo[3.1.0]hexan-2-one; LC, liquid chromatography; LC/MS, liquid chromatography/mass spectrometry; LC/MS/MS, liquid chromatography with tandem mass spectrometric detection; IS, internal standard; DOV 21,947, (+)-1-(3,4-chlorophenyl)-3-azabicyclo[3.1.0]hexane HCl; HPLC, high-performance liquid chromatography; amu, atomic mass units; Cmax, maximum plasma concentration; Tmax, time to reach maximum plasma concentration; t½, terminal phase; λz, terminal phase rate constant; AUC, area under the plasma concentration versus time curve; CL, clearance; Vz, terminal phase volume of distribution; F, absolute bioavailability.
- Received July 26, 2007.
- Accepted October 31, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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