6-Hydroxybuspirone Is a Major Active Metabolite of Buspirone: Assessment of Pharmacokinetics and 5-Hydroxytryptamine_1AReceptor Occupancy in Rats

Abstract

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-OHbuspirone 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 Buspirone ( Fig. 1) is a potent and selective 5-HT 1A receptor partial agonist that has been prescribed for the treatment of generalized anxiety disorders (Sramek et al., 2002;Blier and Ward, 2003;Goodman, 2004). Although the onset of action of buspirone is relatively slow and the efficacy is only obtained after chronic treatment, therapy with buspirone is not associated with undesirable side effects such as sedation, cognitive impairment, withdrawal symptoms, and potential abuse liability that can occur with benzodiazepine treatment (Eison and Temple, 1986;Tunnicliff, 1991;Argyropoulos and Nutt, 1999). Buspirone has also been suggested to have a role in the treatment of depressive disorders (Thase et al., 1998;Blier and Ward, 2003).Current hypotheses on the clinical mechanisms of action of buspirone focus on its agonist activities on 5-HT 1A receptors (Schreiber and De Vry, 1993;Blier and Ward, 2003). Belonging to the superfamily of G-protein-coupled receptors, 5-HT 1A receptors share a high identity (89%) of their transmembrane-spanning amino acid sequences in humans and rats (Albert et al., 1990). They are abundant as presynaptic (somatodendritic) autoreceptors on serotonergic neurons, primarily in the midbrain dorsal raphe nucleus; activation of the 5-HT 1A autoreceptors inhibits the neuronal activity and results in a reduction of 5-HT release in terminal synapses of the serotonergic neurons (Blier and Ward, 2003). 5-HT 1A receptors are also present as postsynaptic receptors in the forebrain limbic structures; activation of these receptors inhibits activities of postsynaptic neurons innervated by serotonergic axonal terminals. It has been hypothesized that prolonged activation of 5-HT 1A autoreceptors in the dorsal raphe with 5-HT 1A agonists, such as buspirone and its analogs, results in desensitization of the receptors and consequently increases releases of 5-HT in the limbic regions (Blier and Ward, 2003). The enhanced serotonergic functions are believed to be responsible for anxiolytic and antidepressant effects of these agents. Although behavioral/clinical effects of buspirone and other 5-HT 1A agonists are believed to be mediated through occupying and acting on 5-HT 1A receptors, the level of 5-HT 1A receptor occupancy required for the effects has not been well investigated. In two human positron emission tomography studies, little or no occupancy of 5-HT 1A receptors has been observed after administration of clinically efficacious doses of buspirone (Rabiner et al., 200...

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“…9). However, in a clinical pharmacokinetic study, it was shown that 6-hydroxybuspirone is present at much greater concentrations than buspirone and may contribute to activity (Dockens et al, 2006;Wong et al, 2007). If it is assumed that the free fraction of this metabolite is equivalent to buspirone itself, then it can be estimated that the metabolite contributes seven times the activity of the parent.…”

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