Received for publication March 19, 2007.
Revised May 3, 2007.
Accepted for publication May 8, 2007.

6-OH Buspirone is a Major Active Metabolite of Buspirone: Assessment of Pharmacokinetics and 5-HT1A Receptor Occupancy in Rats

Abstract

The pharmacokinetics and in vivo potency of 6-OH buspirone, a major metabolite of buspirone, was 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 was similar to that of buspirone. Bioavailability was higher for 6-OH buspirone (19%) when compared to buspirone (1.4%). Following intravenous infusions to steady-state levels in plasma, 6-OH buspirone and buspirone increased 5-HT_1A receptor occupancy in a concentration dependent manner with EC₅₀ values of 1.0 ± 0.3 µM and 0.38 ± 0.06 µM in the dorsal raphe and 4.0 ± 0.6 µM 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 likely contributes to the clinical efficacy of buspirone as an anxiolytic agent.

Key words: CNS pharmacokinetics, pharmacokinetic/pharmacodynamic modeling, pharmacokinetics

This article has been cited by other articles:

				M. Yamauchi, J. Dostal, H. Kimura, and K. P. Strohl Effects of buspirone on posthypoxic ventilatory behavior in the C57BL/6J and A/J mouse strains J Appl Physiol, August 1, 2008; 105(2): 518 - 526. [Abstract] [Full Text] [PDF]