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Pharmacokinetics, Disposition, and Metabolism of Bicifadine in Humans

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

(Received July 26, 2007; Accepted November 5, 2007)

	Abstract

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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 [¹⁴C]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.

Bicifadine (Fig. 1) is being developed for the treatment of neuropathic pain. It inhibits NE (IC₅₀, 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 (tonic) phases of paw-licking in the formalin test using rats and mice, unlike duloxetine or COX inhibitors, which are active only on the late stage (Iyengar et al., 2004). It is not an inhibitor of either COX-1 or COX-2 (Basile et al., 2007) and does not induce dependence in either rodents or primates after as much as 48 days of administration (A. Basile and J. Tizzano, unpublished observations). 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); studies in humans with diabetic neuropathy are ongoing.

View larger version (7K): [in this window] [in a new window]   FIG. 1. Structure of bicifadine. The asterisk indicates the location of the 14C-radiolabel.

	Materials and Methods

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Radiolabeled Bicifadine and Dosage Form. [¹⁴C]Bicifadine was synthesized by ViTrax (Placentia, CA) and supplied as a bulk powder with a specific activity of 0.52 µCi/mg. The radiochemical purity was 99.9% as determined by HPLC. The compound was formulated by Covance Clinical Research on the morning of dosing. [¹⁴C]Bicifadine powder was dissolved in sterile water for irrigation to produce a solution with a concentration of 91.9 mg/g. The appropriate volume was divided into three 00 capsules, which were then double-encapsulated in 000 capsules. The capsules were administered within 20 min of preparation. The mean dose and amount of radioactivity administered was 201 mg (range, 201–202) and 105 µCi (range, 104–105 µCi), respectively.

View larger version (11K): [in this window] [in a new window]   FIG. 2. Concentration of radioactivity (plasma and blood), bicifadine, and the lactam metabolite M12 following a single oral dose of 200 mg of [14C]bicifadine in solution to healthy adult male subjects (n = 8).

Eight healthy male subjects (seven white and one African-American) participated in the study. The subjects had a mean age of 26.4 years (range, 19–43 years), a mean weight of 79.4 kg (range, 61.3–93.2 kg), a mean body mass index of 25.5 kg/m² (range, 20.2–28.6 kg/m²), and met all of the eligibility criteria. Subjects were in good health based on their medical history, a physical examination, a 12-lead electrocardiogram, and clinical laboratory test results. The mean hematocrit was 44 ± 1%. After an overnight fast, the subjects ingested the [¹⁴C]bicifadine in three capsules with 240 ml of water. They were fed a standard lunch approximately 4 h after dosing. The subjects were confined to the study site until at least 168 h postdose, at least 90% of the administered radioactivity was recovered, or until their excreta contained nondetectable amounts of radioactivity for at least 48 h. Samples were collected for 168 h for five subjects and 192 h for the other three subjects.

View larger version (8K): [in this window] [in a new window]   FIG. 3. Cumulative recovery of radioactivity in healthy adult male subjects following a single oral dose of 200 mg of [14C]bicifadine to healthy adult male subjects (n = 8).

Urine was collected predose and at intervals of 0 to 4 h, 4 to 8 h, 8 to 24 h, and at 24-h intervals thereafter up to 192 h postdose. Samples were refrigerated until the end of the block collection periods when the total volume of each urine block was recorded. Samples were stored at –70°C.

All bowel movements and fecal wipes were collected before administration of [¹⁴C]bicifadine and at 24-h intervals up to 192 h postdose. The fecal samples were refrigerated until assayed for total radioactivity; the wipes were not assayed. After homogenization and sampling, the remainder of the sample was stored at approximately –20°C until extracted for metabolite profiling.

Radioactivity Assay. All samples were assayed on a daily basis for total radioactivity by liquid scintillation counting using a Packard model 2900TR Liquid Scintillation Counter (PerkinElmer Life and Analytical Sciences, Boston, MA). Plasma and urine samples (0.2 ml) were added to Ultima Gold XR scintillation cocktail and counted. Blood and fecal homogenates (0.2 g) were oxidized in a Packard model 307 Sample Oxidizer; the resulting ¹⁴CO₂ was trapped in a mixture of Perma Fluor and Carbo-Sorb (PerkinElmer Life and Analytical Sciences,). Samples with less than 2x the background dpm were recorded as zero.

View larger version (10K): [in this window] [in a new window]   FIG. 4. HPLC chromatogram of plasma radioactivity from male subjects at 0.5 h (top) and 4 h (bottom) following a single oral dose of 200 mg of [14C]bicifadine. Both chromatograms are from pooled plasma at the two time points.

Pharmacokinetic Analysis. Blood and plasma concentrations of radioactivity, bicifadine, and M12 above their respective lower limit of quantitation were used for pharmacokinetic analyses using noncompartmental methods (Gibaldi and Perrier, 1982). WinNonlin, version 4.1 (Pharsight, Mountain View, CA), was used for the calculations. The values of C_max and T_max were the observed values for each subject. AUC_0-t was determined using the linear trapezoidal rule whenever the concentration data were increasing and the logarithmic trapezoidal rule any time the concentration data were decreasing. The apparent _z was calculated as the negative slope of the log-linear terminal portion of the blood concentration-time curve using linear regression. A minimum of three observations was used to calculate _z. The t was calculated as ln 2/_z. AUC_0-t was extrapolated to infinity (AUC_0-) as AUC_0- = AUC_0-t + C_last/_z, where C_last was the last quantifiable concentration. CL/F of bicifadine was calculated as Dose/AUC_0-. V_z/F was calculated as Dose/(_z x AUC_0-). Variation around the mean is expressed as the standard deviation.

Metabolite Profiling and Identification. Plasma samples (approximately 0.6–1.3 ml) collected from each subject at 0.5, 2, 4, and 6 h postdose were combined to provide a single pooled plasma sample at each time point. Each pool was extracted twice with 3 volumes of acetonitrile and centrifuged. Extraction recoveries ranged from 82.6 to 131%. Each supernatant was evaporated to dryness under a stream of nitrogen and reconstituted in water/acetonitrile (v/v 1:1). The supernatant was dried again and reconstituted in water. Urine samples collected from 0 to 24 h postdose were pooled such that approximately 0.2% of each urine sample was included to prepare a single 0- to 24-h pooled urine sample for each subject. A percentage of each individual's pooled urine was combined for a single overall pooled urine sample for metabolite profiling. After clarification by centrifugation through a centrifugal filtration device, recovery of radioactivity was 102%. Approximately 3% of each fecal homogenate was included in the pools for each individual such that they represented greater than 80% of the amount excreted into feces. Due to differences in the rate of fecal excretion, pooled samples from individuals were profiled separately. Samples were extracted twice with 3 volumes of acetonitrile and centrifuged. The extracts were combined and analyzed by liquid scintillation chromatography; extraction efficiencies were 74 to 83%. Each supernatant was evaporated to dryness under a stream of nitrogen and reconstituted in water/acetonitrile (v/v 1:1). For all samples, extraction and recovery efficiencies were determined by liquid scintillation counting, and corrections were made to subsequent data.

HPLC and Radiometric Detection. The HPLC system used for profiling of metabolites consisted of an HP 1100 series pump, autoinjector, column heater, and ultraviolet detector set to 254 nm (Hewlett Packard, Palo Alto, CA). The column was a Zorbax SB-Phenyl column (250 x 4.6 mm, 5-µm particle size; Agilent Technologies, Santa Clara, CA) with a Phenomenex propylphenyl guard column (4 x 3 mm; Phenomenex, Torrance, CA). The initial mobile phase was 95% 0.05% formic acid in reverse osmosis water/5% acetonitrile. The percentage of acetonitrile increased linearly to 25% over 45 min and then increased linearly to 95% over the next 5 min, where it was held for 6 min. The column was re-equilibrated to the initial conditions over the next 11 min. The flow rate was 1.0 ml/min. Column fractions were collected every 10 s for 62 min using an ISCO Foxy 200 fraction collector (Cole-Parmer Instrument Co., Vernon Hills, IL). The fractions were analyzed using a TopCount Microplate Scintillation and Luminescence counter (Packard Instrument). To determine the percentage of the total dose in each radioactive metabolite from the pooled urine and fecal extracts, the percentage of radioactivity that eluted in each peak was multiplied by the percentage of administered radioactivity excreted in the pooled sample and corrected for extraction and reconstitution recoveries.

Full-scan LC/MS analyses were conducted using an Applied Biosystems 4000 Q Trap with a turbospray source. The mass spectrometer software was Analyst 1.4.1 from Applied Biosystems. The HPLC system was a Shimadzu model SIL-HTc autoinjector and system controller and Shimadzu model LC-10AD VP pumps (Shimadzu, Columbia, MD). A Radiomatic Series 500 with Flo-One software, version 3.65 (PerkinElmer Life and Analytical Sciences), was used for radiochemical detection. The HPLC column, solvents, and gradient were the same as used for metabolite profiling. After passing through the column switcher, the column effluent was split with approximately 25% diverted to the mass spectrometer and 75% to the radiometric detector. To minimize contamination of the mass spectrometer source, the first 4.5 min of each run were diverted to waste. Samples were scanned in the positive-ion full-scan mode from 80 to 700 amu with a Q1 scan time of 0.8 s for 52 min. The ion spray voltage was 5000 V, the source temperature was 500°C, and the exit potential was 10 V. Nitrogen was used as the curtain, nebulizer (GS1), and turbo (GS2) gas. Product-ion analyses used the same instrumentation and conditions as LC/MS with the following exceptions: enhanced product ion was used for the scan function; the ionization mode was positive turbo spray; nitrogen was used as the collision gas; and the collision energy, mass range, and scan time were variable. The contribution of the ¹⁴C-tracer to the mass of the metabolites was low enough (0.15%) 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).

The high-resolution mass spectrum of the ion at the nominal m/z 135 in M9 was obtained using a Thermo LTZ/Orbitrap Fourier transform mass spectrometer (Thermo Fisher Scientific Inc., Waltham, MA). A solution of M9 was infused using an electrospray ionization source. The product ion spectrum was obtained at a resolution of 60,000 and using a lock mass of 218.08117 amu (protonated molecular ion of M9).

	Results

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Pharmacokinetics of Radioactivity, Bicifadine, and M12. The mean concentrations of radioactivity in blood and plasma concentrations of radioactivity, bicifadine, and M12 (DOV 255,828) following a single oral dose of [¹⁴C]bicifadine in solution are presented in Fig. 2. The C_max of radioactivity in plasma was 5154 ng Eq · h/g at 1.19 h (Table 1). Its t was approximately 2.6 h; the last measurable concentration of plasma radioactivity was at 12.0 h postdose. C_max and AUC_0-t values of radioactivity in blood were 53 to 54% of the values in plasma, indicating that bicifadine and its metabolites did not concentrate in red blood cells. The subjects' mean hematocrit of 44% is in agreement with these results.

The C_max of bicifadine, 1780 ng/ml, was observed at 1.06 h postdose (Table 1). Its AUC_0-t was 3373 ng · h/ml, approximately 15% of the total drug equivalents in plasma. Both the t and the time to the last measurable concentration of plasma bicifadine were slightly shorter than for plasma radioactivity. CL/F was 59.1 l/h, and V_z/F was 125 l; based on the weight of the subjects, CL/F was 0.74 ± 0.28 l/h/kg, and V_z/F was 1.58 ± 0.32 l/kg. The lactam metabolite, M12, had a C_max that was slightly lower than that of bicifadine and a T_max that occurred later. Although exposure to M12 was approximately 50% higher compared with that of bicifadine, their t values were similar.

Excretion of Radioactivity. Almost the entire orally ingested radioactivity was excreted into urine (Fig. 3). By 24 h postdose, 87.3 ± 5.3% of the dose was recovered in the urine; another 1.5% was excreted over the next 72 h. Only 3.52% of the dose was excreted into the feces over the collection period. Overall recovery of radioactivity was 92.3 ± 5.2% (range, 88.1–104%). Two subjects had recoveries that were slightly below 90% (88.1 and 89.4%); neither had detectable amounts of radioactivity in their feces and urine from 96 to 192 h postdose.

View larger version (12K): [in this window] [in a new window]   FIG. 5. HPLC chromatogram of radioactivity in pooled urine (0–24 h) (top) and feces (subject 6, 24–120 h) (bottom) from male subjects following a single oral dose of 200 mg of [14C]bicifadine. The urine was a pooled sample from all eight subjects. Feces from individual subjects were profiled due to differing times for excretion of radioactivity.

View larger version (8K): [in this window] [in a new window]   FIG. 6. Proposed metabolic scheme of bicifadine in adult male subjects.

Urine. The major urinary metabolite was the lactam acid M9; it constituted 55.6% of the administered radioactivity (Table 3; Fig. 5). A series of smaller peaks that corresponded to the acyl glucuronide of M9 and its rearrangement products eluted with R_t values ranging from 18.8 to 23.2 min. These peaks represented 7.3% of the dose and, together with M9, accounted for 62.9% of the dose. The other carboxylic acid-containing metabolite, M3, and its acyl glucuronide(s), M14A-F, were also detected in urine. Combined, M3 and its conjugate accounted for another 22.4% of the dose. A smaller unidentified peak, M32, eluted at an R_t of 31.7 min, but it represented only 0.57% of the dose. Unchanged bicifadine and the lactam M12 were not detectable in the pooled urine.

Feces. M3 and M9 represented most of the radioactivity in feces (0.85 and 1.34% of the dose, respectively) (Table 3; Fig. 5). Two other unidentified metabolites, with R_t values of 46.0 and 50.6 min, accounted for <0.4% of the dose.

Metabolite Structure Identification. The proposed metabolic scheme for bicifadine in humans is displayed in Fig. 6.

Bicifadine, M9, and M12. The product-ion mass spectra of bicifadine, M9, and M12 in the pooled plasma collected 4 h after the oral dose of [¹⁴C]bicifadine were essentially identical to the mass spectra of the corresponding standards (Table 4). The HPLC retention times of the plasma peaks were also the same as the standards.

The high-resolution mass spectrum of the ion at m/z 135 in the product-ion mass spectrum of M9 was also determined. The fragment had an observed amu of 135.04405; the calculated amu for is 135.04406. The difference between the calculated and observed amu was 0.07 ppm. This empirical formula corresponds to an ion with the structure HO₂C-phenyl-. Two other possible formulas with a nominal amu of 135 were and C₈ H₉NO⁺, but their calculated molecular weights were 269 and 176 ppm higher, respectively, than the observed. 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).

View larger version (12K): [in this window] [in a new window]   FIG. 7. Enhanced product-ion mass spectrum of M3 (left) and M31B (right), an acyl glucuronide conjugate of M9, in pooled plasma collected 4 h after administration of [14C]bicifadine. The bottom panels are the proposed fragmentation patterns of the two metabolites.

M14A-F (M3 Acyl Glucuronides). A series of peaks eluted between 5.24 and 8.42 min in the extract of the 0- to 24-h pooled urine sample. The [M+H]⁺ of all peaks was at 380 amu, 176 amu (glucuronic acid) higher than M3. The ion at m/z 204 was due to the loss of the glucuronic acid moiety. It could not be determined which of the six peaks was the initial 1-O-β-acyl glucuronide.

M31B-F (M9 Acyl Glucuronides). The metabolites M31B-F (R_t, 18.8–23.2 min) all had an [M+H]⁺ at 394 amu, 176 amu (glucuronic acid) higher than that of M9 (Fig. 7). They all had product ions at m/z 218 (–glucuronic acid), 200 (m/z 218 – water), and 171, which were also detected in the spectrum of M9.

M32, M33, and M34. The urine and feces contained three minor metabolites for which mass spectra could be obtained, but possible structures were not identified. M32 had an [M+H]⁺ at 366, 192 amu higher than that of bicifadine. The ions at m/z 190 and 105 indicated the loss of glucuronic acid and that the methyl group had not been oxidized, respectively. M33 was detected in fecal samples and had an [M+H]⁺ of 232, 58 amu higher than that of bicifadine. Its enhanced product-ion spectrum was similar to M3. M34 (R_t, 49.7 min) had an [M+H]⁺ at m/z 174 and enhanced product-ion MS that was virtually identical to the bicifadine standard, but its R_t of 49.7 min indicated that it had a different structure. Two other metabolites, constituting <0.4% of the dose, with R_t values of approximately 30 and 50 min were detected in fecal extracts, but reliable mass spectra could not be obtained.

Safety. There were 28 adverse events that were either possibly or probably related to the study drug; they were all mild or moderate in severity. There were no clinically significant changes or abnormalities in the clinical laboratory evaluations, vital sign measurements, physical examinations, or 12-lead electrocardiograms in the study. Overall, the compound was well tolerated.

	Discussion

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When [¹⁴C]bicifadine was administered as an oral solution, the C_max of both bicifadine and total drug equivalents was approximately 1 h. The elimination half-life of unchanged parent drug was 1.6 h. The material used in clinical trials is a sustained release formulation with a significantly longer half-life (N. Huang, unpublished observations).

The oral clearance of bicifadine in this study was 59 l/h. The plasma flow of the human liver is approximately 48 l/h (Davies and Morris, 1993), slightly less than the oral clearance of bicifadine. Extrahepatic clearance of the compound is likely since the main route of metabolism is formation of the lactam metabolite by monoamine oxidase B (Erickson et al., 2007), which is widely distributed in the body (Cesura and Pletscher, 1992).

Exposure to unchanged bicifadine, based on values of AUC_0-t, accounted for approximately 15% of the total drug-derived radioactivity. The rest of the plasma radioactivity was due predominantly to M12 and the two carboxylic acids, M3 and M9. At 4 h postdose, these two acids were the predominant peaks in plasma. 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).

Bicifadine was well absorbed, with approximately 89% of the dose recovered in the urine. The small amount in the feces was composed only of metabolites. Neither unchanged bicifadine nor M12 were detected in urine or feces.

M9 and its glucuronide accounted for 64.3% of the radioactive dose in the excreta over the 192-h study period, whereas M3 and its glucuronide represented another 23.3% of the dose. It was not determined which of the M14 peaks was the initial 1-O-acyl-β-glucuronide, which is known to rearrange at neutral to slightly basic pH (Compernolle et al., 1978; Hasegawa et al., 1982; Janssen et al., 1982). Monkeys and humans produced the glucuronide conjugate of M9 (M31B-F), but rats and mice did not (Musick et al., 2008).

In conclusion, bicifadine was well absorbed by humans when administered as an oral solution. The T_max of radioactivity and bicifadine was approximately 1 h. Most of the drug-derived radioactivity in plasma was due to metabolites, especially the lactam M12, the acid M3, and the lactam acid M9. Most of the radioactivity was recovered in urine in the first 24 h. M9 and its acyl glucuronide conjugate accounted for almost two-thirds of the dose; M3 and its glucuronide represented another 23% of the dose. No human-specific metabolites were identified, and the compound was well tolerated by the subjects with no reported serious or severe adverse events.

	Footnotes

 
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

doi:10.1124/dmd.107.017871.

ABBREVIATIONS: NE, norepinephrine; 5-HT, serotonin; DA, dopamine; DOV 220,075, (±)-1-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane HCl (bicifadine); COX, cyclooxygenase; HPLC, high-performance liquid chromatography; DOV 255,828, 5-(4-methylphenyl)-3-azabicyclo[3.1.0]hexan-2-one; LC, liquid chromatography; MS, mass spectrometry; AUC, area under the plasma concentration versus time curve; C_max, maximum plasma concentration; T_max, time to reach maximum plasma concentration; CL/F, apparent oral clearance; V_z,/F, terminal phase apparent oral volume of distribution; t, elimination phase half-life; _z, terminal phase rate constant; amu, atomic mass unit; R_t, HPLC column retention time.

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

	References

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Ascher JA, Cole JO, Colin JN, Feighner JP, Ferris RM, Fibiger HC, Golden RN, Martin P, Potter WZ, Richelson E, et al. (1995) Bupropion: a review of its mechanism of antidepressant activity. J Clin Psychiatry 56: 395–401.[Medline]

Basile AS, Janowsky A, Golembiowska K, Kowalska M, Tam E, Benveniste M, Popik P, Nikiforuk A, Krawczyk M, Nowak G, et al. (2007) Characterization of the antinociceptive actions of bicifadine in models of acute, persistent, and chronic pain. J Pharmacol Exp Ther 321: 1208–1225.[Abstract/Free Full Text]

Cesura AM and Pletscher A (1992) The new generation of monoamine oxidase inhibitors. Prog Drug Res 38: 171–297.[Medline]

Compernolle F, Van Hees GP, Blanckaert N, and Heirwegh KP (1978) Glucuronic acid conjugates of bilirubin-IXalpha in normal bile compared with post-obstructive bile. Transformation of the 1-O-acylglucuronide into 2-, 3-, and 4-O-acylglucuronides. Biochem J 171: 185–201.[Medline]

Davies B and Morris T (1993) Physiological parameters in laboratory animals and humans. Pharm Res 10: 1093–1095.[CrossRef][Medline]

Erickson DA, Hollfelder S, Tenge J, Gohdes M, Burkhardt JJ, and Krieter PA (2007) In vitro metabolism of the analgesic bicifadine in the mouse, rat, monkey, and human. Drug Metab Dispos 35: 2232–2241.[Abstract/Free Full Text]

Gibaldi M and Perrier D (1982) Pharmacokinetics, 2nd ed, Marcel Dekker, Inc., New York.

Hasegawa J, Smith PC, and Benet LZ (1982) Apparent intramolecular acyl migration of zomepirac glucuronide. Drug Metab Dispos 10: 469–473.[Abstract]

Iyengar S, Webster AA, Hemrick-Luecke SK, Xu JY, and Simmons RMA (2004) Efficacy of duloxetine, a potent and balanced serotonin-norepinephrine reuptake inhibitor in persistent pain models in rats. J Pharmacol Exp Ther 311: 576–584.[Abstract/Free Full Text]

Janssen FW, Kirkman SK, Fenselau C, Stogniew M, Hofmann BR, Young EM, and Ruelius HW (1982) Metabolic formation of N- and O-glucuronides of 3-(p-chlorophenyl)thiazolo[3,2-a]benzimidazole-2-acetic acid. Rearrangement of the 1-O-acyl glucuronide. Drug Metab Dispos 10: 599–604.[Abstract]

Musick TJ, Gohdes M, Duffy A, Erickson DA, and Krieter PA (2008) Pharmacokinetics, disposition, and metabolism of the analgesic bicifadine in the mouse, rat, and monkey. Drug Metab Dispos 36: 241–251.[Abstract/Free Full Text]

Riff D, Huang N, Czobor P, and Stern W (2006) A five-day, multi-center, randomized, placebo-controlled, double-blind, efficacy and safety study of bicifadine and tramadol versus placebo in the treatment of postoperative bunionectomy pain. J Pain 7 (Suppl 2): S40.

Semenchuck MR, Sherman S, and Davis B (2001) Double-blind, randomized trial of bupropion SR for the treatment of neuropathic pain. Neurology 57: 1583–1588.[Abstract/Free Full Text]

Sindrup SH, Otto M, Finnerup NB, and Jensen TS (2005) Antidepressants in the treatment of neuropathic pain. Basic Clin Pharmacol Toxicol 96: 399–409.[CrossRef][Medline]

Stern W, Czobor P, Stark J, and Krieter P (2005) Relationship between plasma bicifadine levels and analgesic effect in a dental pain model, in Abstracts: 11th World Congress on Pain; 2005 Aug 21–26; Sydney, Australia; pp 111, International Association for the Study of Pain, Seattle.

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