Disposition and Metabolism of [C]Brasofensine in Rats, Monkeys, and Humans

Brasofensine is an inhibitor of the synaptic dopamine transporter. These studies were conducted to characterize the pharmacokinetics, absolute bioavailability, disposition, and metabolism of brasofensine after i.v. and/or p.o. administrations of [C]brasofensine in rats (1.5 mg/kg i.v., 4 mg/kg p.o.) and monkeys (4 mg i.v., 12 mg p.o.) and humans (50 mg p.o.). Brasofensine was rapidly absorbed after p.o. administration in rats and monkeys, with peak plasma concentrations occurring 0.5 to 1 h but 3 to 8 h for brasofensine in humans. Plasma terminal elimination half-lives were 2 h in rats, 4 h in monkeys, and 24 h in humans. Total body clearance and steady-state volume of distribution values were 199 ml/min/kg and 24 l/kg, respectively, in the rat and 32 ml/min/kg and 46 l/kg, respectively, in the monkey. Absolute bioavailability was 7% in rats and 0.8% in monkeys. After a single p.o. dose, urinary excretion of radioactivity accounted for 20% of the administered dose in rats, 70% in monkeys, and 86% in humans, with the remainder excreted into the feces. Brasofensine had extensive first-pass metabolism following p.o. administration in humans, monkeys, and rats. It primarily underwent Oand N-demethylation and isomerization. Some of the desmethyl metabolites were further converted to glucuronides. These primary metabolites and glucuronides of demethyl brasofensine (M1 and M2) were major circulating metabolites in humans and were also observed in rat and monkey plasma. Brasofensine (BMS-204756) is a novel inhibitor of the synaptic dopamine transporter and has potential use in Parkinson’s disease (Johnston and Brotchie, 2004), a disease estimated to affect approximately 500,000 persons in the United States alone (Battistin et al., 1996; Brooks, 1997). It is known that nigrostriatal dopamine loss is the major factor in Parkinson’s disease pathogenesis, with clinical symptoms of parkinsonism beginning when there is approximately 80% depletion of the striatal dopamine (Kish et al., 1988). Over time, those with Parkinson’s disease have a degeneration of the dopaminergic neurons, causing a continued depletion of the amount of dopamine released. This exaggerates the symptoms of parkinsonism, and it is thought that this progression of symptoms could be slowed by inhibition of the dopamine transporter (Mouradian et al., 1987). The dopamine transporter actively transports released dopamine from the synaptic cleft back into the presynaptic nerve terminal where it is metabolized by monoamine oxidase or extracellularly by catechol-Omethyltransferase. Inhibition of the dopamine transporter (dopamine reuptake inhibition) enhances the effectiveness of the diminishing amounts of dopamine that are released into the synaptic cleft. Thus, the primary role of brasofensine is to conserve the greatly reduced level of endogenous dopamine within the synaptic cleft and also to extend the potency and duration of action of exogenous dopamine from the administration of levodopa. This appears to be true in a marmoset model of Parkinson’s disease (Pearce et al., 2002) but has not yet been shown in the clinic (Frackiewicz et al., 2002). The main objectives of these studies were to 1) assess the pharmacokinetics and absolute bioavailability of brasofensine in rats, monkeys, and humans; 2) investigate biotransformation of brasofensine in rats and monkeys; and 3) compare the disposition and plasma metabolite profiles of brasofensine in rats, monkeys, and humans after p.o. and/or i.v. administrations of radiolabeled brasofensine. Materials and Methods Chemicals. Radiolabeled [C]brasofensine (Fig. 1) as the maleate salt had a radiochemical purity of 97.6% and specific activity of 50 Ci/mg free base. [C]Brasofensine, unlabeled brasofensine, unlabeled BMS-205912, and metabolite standards [O-desmethyl brasofensine (ODME), O-desmethyl BMSPart of this work was presented at the 9th North American ISSX Meeting, Nashville, TN, October 24–28, 1999. Article, publication date, and citation information can be found at http://dmd.aspetjournals.org. doi:10.1124/dmd.107.016139. ABBREVIATIONS: brasofensine, BMS-204756, ( )-(E)-(1R,2R,3S)-3-(3,4-dichlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carbaldehyde Omethyloxime; BMS-205912, ( )-(Z)-(1R,2R,3S)-3-(3,4-dichlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carbaldehyde O-methyloxime; BMS-180448, (3S-trans)-N-(4-chlorophenyl)-N'-cyano-N -(6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl)guanidine; BMS217380, N,N-diethyl-2-[4-(phenylmethyl-14C)phenoxy]ethanamine, monohydrochloride; BMS-181101, 5-fluoro-3-[3-[4-(5-methoxy-4-pyrimidinyl)-1-piperazinyl]propyl]-1H-indole; ODME, O-desmethyl brasofensine; ODMZ, O-desmethyl BMS-205912; NDME, N-desmethyl brasofensine; BMS, Bristol-Myers Squibb; LE, Long Evans; BDC, bile duct–cannulated; LC/MS, liquid chromatography/mass spectrometry; MS/MS, tandem mass spectrometry; QC, quality control; LLQ, lower limit of quantitation; CSF, cerebrospinal fluid; HPLC, high-performance liquid chromatography; AUCINF, area under the plasma concentration-time curve from 0 to infinity; CLT, total body clearance; Vdss, steady-state volume of distribution; AUMC, area under the first moment curve; MRT, mean residence time(s); amu, atomic mass unit(s). 0090-9556/08/3601-24–35$20.00 DRUG METABOLISM AND DISPOSITION Vol. 36, No. 1 Copyright © 2008 by The American Society for Pharmacology and Experimental Therapeutics 16139/3282598 DMD 36:24–35, 2008 Printed in U.S.A. 24 at A PE T Jornals on A uust 7, 2017 dm d.aspurnals.org D ow nladed from