RT Journal Article SR Electronic T1 6-Hydroxybuspirone Is a Major Active Metabolite of Buspirone: Assessment of Pharmacokinetics and 5-Hydroxytryptamine1A Receptor Occupancy in Rats JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 1387 OP 1392 DO 10.1124/dmd.107.015768 VO 35 IS 8 A1 Harvey Wong A1 Randy C. Dockens A1 Lori Pajor A1 Suresh Yeola A1 James E. Grace, Jr. A1 Arlene D. Stark A1 Rebecca A. Taub A1 Frank D. Yocca A1 Robert C. Zaczek A1 Yu-Wen Li YR 2007 UL http://dmd.aspetjournals.org/content/35/8/1387.abstract AB 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 EC50 values of 1.0 ± 0.3 and 0.38 ± 0.06 μMinthe dorsal raphe and 4.0 ± 0.6 and 1.5 ± 0.3 μM in the hippocampus, respectively. Both compounds appeared to be ∼4-fold more potent in occupying presynaptic 5-HT1A 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 ∼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. The American Society for Pharmacology and Experimental Therapeutics