Pharmacokinetics, Disposition, and Metabolism of Bicifadine in Humans

Abstract

ABSTRACT:Bicifadine [DOV 220,075; (؎)-1-(4-methylphenyl)-3-azabicyclo-[3.1.0]hexane HCl)] is a non-narcotic analgesic that has proven to be effective for the treatment of acute pain in clinical studies. The pharmacokinetics, disposition, and metabolism of bicifadine were determined in eight healthy adult male subjects following a single oral dose of 200 mg of [ 14 C]bicifadine in solution. The maximum concentration of total drug equivalents and bicifadine in plasma was at approximately 1 h; the elimination half-life was 2.6 and 1.6 h for radioactivity and bicifadine, respectively. Unchanged bicifadine represented 15% of the area under the concentration-time curve for total drug equivalents; the rest was due mainly to the lactam (M12), the acid (M3), and the lactam acid (M9). Total recovery of the dose was 92%, with most of the radioactivity recovered in the urine in the first 24 h; fecal excretion accounted for only 3.5% of the dose. Approximately 64% of the dose was metabolized to M9 and its acyl glucuronide; another 23% was recovered as M3 and its acyl glucuronide. Neither bicifadine nor M12 were detected in urine or feces. There were no reported serious or severe adverse events during the study.Chronic peripheral neuropathic pain is difficult to treat, and side effects may limit the usefulness of a drug. Although opiates have been used for neuropathic pain management, tolerance develops to their analgesic efficacy, and they cause drowsiness and constipation. Empirical observations have demonstrated the efficacy of tricyclic antidepressants in treating peripheral neuropathy (Sindrup et al., 2005). Research has shown that this effect is produced by inhibition of the neuronal reuptake of NE and 5-HT and blocks the postsynaptic ␣-adrenergic, H 1 -histaminergic, and muscarinic cholinergic receptors. Duloxetine is a selective 5-HT and NE reuptake inhibitor that has been approved for treatment of diabetic neuropathy. Bupropion is a weak blocker of NE and DA, but not 5-HT, reuptake (Ascher et al., 1995) but was effective in reducing neuropathic pain in patients with human immunodeficiency virus (Semenchuck et al., 2001). The involvement of DA in analgesic mechanisms suggests that a broadened analgesic range may result from the ability to enhance dopaminergic neurotransmission, in addition to activating serotonergic and noradrenergic pathways. Thus, agents that simultaneously inhibit DA, NE, and 5-HT transporters may possess a unique analgesic profile, Bicifadine (Fig. 1) is being developed for the treatment of neuropathic pain. It inhibits NE (IC 50 , 55 nM) and 5-HT (117 nM) reuptake, with lesser potency in blocking DA reuptake (910 nM), as determined using recombinant human transporter systems (Basile et al., 2007). In vivo microdialysis studies in the brains of rats indicate that bicifadine increases the extracellular levels of all three neurotransmitters following oral administration of analgesic doses (Basile et al., 2007). Bicifadine was an effective antinociceptive agent in both the early (acute) and late (ton...

SLC6 Neurotransmitter Transporters: Structure, Function, and Regulation

“…Bicifadine (Fig. 11) is a potent inhibitor of SERT and NET and is currently in development against neuropathic pain (Krieter et al, 2008). It is noteworthy that bicifadine also possess inhibitory activity against DAT (Basile et al, 2007), which indicates that inhibition of all three monoamine transporters might provide a novel and efficacious strategy for the treatment of neuropathic pain.…”

Non-Response to Initial Antidepressant Therapy

“…Several open-label randomized controlled clinical trials, meta-analyses, and systematic reviews have confirmed the clinical efficacy of selected antidepressants in persistent pain conditions (Dharmshaktu et al, 2011). Clinical studies have corroborated that bicifadine is an effective analgesic in the treatment of postoperative pain (Krieter et al, 2008). In a second study, the TRI NS7051, has shown comparable antinociceptive properties to tramadol confirming the interest of these antidepressants in the relief of pain (Munro et al, 2008).…”

A New Class of Antidepressant Drugs in the Treatment of Psychiatric Disorders: The Triple Reuptake Inhibitors

“…Mechanical hyperalgesia was also reduced by bicifadine in the STZ model of neuropathic pain (Basile et al, 2007). Clinical (phase II/III) studies have demonstrated that bicifadine is an effective analgesic in the treatment of postoperative pain (Krieter et al, 2008). The impact of bicifadine on 5-HT, NE and DA neurotransmissions was confirmed by in vitro binding assays and intracerebral in vivo microdialysis study in freely moving rats.…”