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Pharmacokinetics, Disposition and Metabolism of Bicifadine in the Mouse, Rat and Monkey (Musick et a

Pharmacokinetics, Disposition and Metabolism of Bicifadine in the Mouse, Rat and Monkey (Musick et a

  1. Jatelka
    DRUG METABOLISM AND DISPOSITION Vol. 36, No. 2

    Timothy J. Musick, Mark Gohdes, Andrea Duffy, David A. Erickson, and Philip A. Krieter

    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 pharmacokinet-ics, 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 con-centration-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 radio-activity 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.