title: 6-Hydroxybuspirone is a major active metabolite of buspirone: assessment of pharmacokinetics and 5-hydroxytryptamine1A receptor occupancy in rats.
abstract: The pharmacokinetics and in vivo potency of 6-hydroxybuspirone (6-OH-buspirone), a major metabolite of buspirone, were investigated. The plasma clearance (47.3 +/- 3.5 ml/min/kg), volume of distribution (2.6 +/- 0.3 l/kg), and half-life (1.2 +/- 0.2 h) of 6-OH-buspirone in rats were similar to those for buspirone. Bioavailability was higher for 6-OH-buspirone (19%) compared with that for buspirone (1.4%). After intravenous infusions to steady-state levels in plasma, 6-OH-buspirone and buspirone increased 5-hydroxytryptamine (HT)(1A) receptor occupancy in a concentration-dependent manner with EC(50) values of 1.0 +/- 0.3 and 0.38 +/- 0.06 microM in the dorsal raphe and 4.0 +/- 0.6 and 1.5 +/- 0.3 microM in the hippocampus, respectively. Both compounds appeared to be approximately 4-fold more potent in occupying presynaptic 5-HT(1A) receptors in the dorsal raphe than the postsynaptic receptors in the hippocampus. Oral dosing of buspirone in rats resulted in exposures (area under the concentration-time profile) of 6-OH-buspirone and 1-(2-pyrimidinyl)-piperazine (1-PP), another major metabolite of buspirone, that were approximately 12 (6-OH-buspirone)- and 49 (1-PP)-fold higher than the exposure of the parent compound. As a whole, these preclinical data suggest that 6-OH-buspirone probably contributes to the clinical efficacy of buspirone as an anxiolytic agent.
authors.affiliation: Department of Metabolism and Pharmacokinetics, Pharmaceutical Research Institute, Bristol-Myers Squibb, Wallingford, Connecticut 06492-7660, USA.
authors.forename: Harvey
authors.initials: H
authors.lastname: Wong
authors.forename: Randy C
authors.initials: RC
authors.lastname: Dockens
authors.forename: Lori
authors.initials: L
authors.lastname: Pajor
authors.forename: Suresh
authors.initials: S
authors.lastname: Yeola
authors.forename: James E
authors.initials: JE
authors.lastname: Grace
authors.forename: Arlene D
authors.initials: AD
authors.lastname: Stark
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Taub
authors.forename: Frank D
authors.initials: FD
authors.lastname: Yocca
authors.forename: Robert C
authors.initials: RC
authors.lastname: Zaczek
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Li
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001345:Autoradiography; D001682:Biological Availability; D002065:Buspirone / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D015394:Molecular Structure; D010879:Piperazines / Q000378:metabolism; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011725:Pyridines / Q000378:metabolism; D011903:Raphe Nuclei / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D014316:Tritium
chemical_list: D010879:Piperazines; D011725:Pyridines; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists; D014316:Tritium; D044282:Receptor, Serotonin, 5-HT1A; C052140:1-(2-pyridinyl)piperazine; C516840:6-hydroxybuspirone; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D002065:Buspirone