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6-Hydroxybuspirone Is a Major Active Metabolite of Buspirone: Assessment of Pharmacokinetics and 5-Hydroxytryptamine_1A Receptor Occupancy in Rats

Departments of Metabolism and Pharmacokinetics (H.W., L.P., J.E.G.), Clinical Discovery (R.C.D.), Biotransformation (S.Y.), and Neuroscience Biology (A.D.S., R.A.T., F.D.Y., R.C.Z., Y.W.L.), Pharmaceutical Research Institute, Bristol-Myers Squibb, Wallingford, Connecticut

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-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 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.

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