Pharmacokinetics, Disposition, and Metabolism of Bicifadine in the Mouse, Rat, and Monkey

Abstract

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. [ 14 C]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 [ 14 C]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.Bicifadine (Fig. 1) is an inhibitor of norepinephrine and serotonin uptake that is being developed for the treatment of acute and chronic pain. The compound is a non-narcotic analgesic (Epstein et al., 1982) that is active in preclinical models of neuropathic pain. In animals, bicifadine has been shown to inhibit dopamine uptake, thus making it a functional triple reuptake inhibitor with antinociceptive and antiallodynic activity in acute, persistent, and chronic pain models (Basile et al., 2007). Clinically, it has been shown to be effective in the treatment of acute dental (Stern et al., 2005) and bunionectomy pain (Riff et al., 2006).The metabolites of bicifadine formed by mouse, rat, monkey, and human hepatocytes and microsomes were reported previously (Erickson et al., 2007). The two main metabolic pathways in all four species were formation of a lactam and the oxidation of the tolylmethyl group. When tested in human in vitro systems, MAO-B was the principal enzyme that formed the lactam, whereas CYP2D6 was responsible for the initial hydroxylation of the tolylmethyl group. The present studies were performed to determine the pharmacokinetics, metabolism, and disposition of bicifadine in the mouse, rat, and monkey, the species used in toxicological and carcinogenicity studies. Materials and MethodsChemicals and Reagents. [ Animal Studies. All experim...

Pharmacokinetics, Disposition, and Metabolism of Bicifadine in Humans

“…A similar fragmentation mechanism was observed for bicifadine (m/z 105), M3 (m/z 135) (Fig. 7), and M2 (m/z 121) (Musick et al, 2008).…”

“…The concentration of M12 had declined by 4 h, whereas the concentration of bicifadine was minor. No acyl glucuronide conjugate of M3 was detected in human plasma as it was in mouse (Musick et al, 2008).…”

“…The contribution of the 14 C-tracer to the mass of the metabolites was low enough (ϳ0.15%) so that it did not contribute to the m/z ratios as determined by mass spectrometry. For consistency across studies, the metabolite numbering system is the same as that used in the in vitro and nonclinical metabolism studies (Erickson et al, 2007;Musick et al, 2008).…”

“…In addition to assaying the plasma concentrations of total drug equivalents and unchanged bicifadine, the mass balance of drug-derived radioactivity in the urine and feces was determined. Metabolites in the plasma, urine, and feces were identified and compared with those formed in vitro (Erickson et al, 2007) and in the species used for toxicology studies (Musick et al, 2008). …”

“…The analysis of plasma samples for bicifadine and M12 (DOV 255,828) were performed using a validated liquid chromatography (LC)/tandem mass spectrometery assay as detailed in the companion article on page 241 of this issue (Musick et al, 2008). The only changes were that 0.5 ml of plasma was assayed and a Symbiosis Pharma System (Spark Holland Inc., Plainsboro, NJ) was used.…”