TY - JOUR T1 - 6-Hydroxybuspirone Is a Major Active Metabolite of Buspirone: Assessment of Pharmacokinetics and 5-Hydroxytryptamine<sub>1A</sub> Receptor Occupancy in Rats JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1387 LP - 1392 DO - 10.1124/dmd.107.015768 VL - 35 IS - 8 AU - Harvey Wong AU - Randy C. Dockens AU - Lori Pajor AU - Suresh Yeola AU - James E. Grace, Jr. AU - Arlene D. Stark AU - Rebecca A. Taub AU - Frank D. Yocca AU - Robert C. Zaczek AU - Yu-Wen Li Y1 - 2007/08/01 UR - http://dmd.aspetjournals.org/content/35/8/1387.abstract N2 - 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 ER -