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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

(Received March 16, 2007; accepted May 8, 2007)

	Abstract

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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.

View larger version (7K): [in this window] [in a new window]   FIG. 1. Chemical structure of buspirone and 6-OH-buspirone.

In humans and rats, buspirone is extensively metabolized and has low oral bioavailability (<5%) (Caccia et al., 1983; Jajoo et al., 1989). The metabolic disposition is similar in the two species with three major metabolic pathways being N-dealkylation to 1-(2-pyrimidinyl)-piperazine (1-PP) and hydroxylation to either 5-hydroxybuspirone or 6-hydroxybuspirone (Fig. 1). Of these metabolites, 1-PP has been the most extensively investigated in its role as an active metabolite (Caccia et al.,1986; Zuideveld et al., 2002). 1-PP behaves as an ₂-adrenoceptor antagonist with a low affinity to the 5-HT_1A receptor (Caccia et al., 1986; Gobbi et al., 1991) and therefore is unlikely to play an important role in the anxiolytic effects of buspirone. Much less is known about the pharmacological properties of 6-OH-buspirone. Conversion to 6-OH-buspirone has been shown to be the predominant metabolic pathway involved in buspirone elimination in human liver microsomes (Zhu et al., 2005). In addition, plasma levels of 6-OH-buspirone have been recently reported to be 40-fold greater than those of buspirone after oral administration to humans (Dockens et al., 2006). More recently, 6-OH-buspirone has been found to possess anxiolytic activity in rats using the fear-induced ultrasonic vocalization paradigm (A. D. Stark, unpublished observations). The primary aims of the present study were 1) to evaluate the pharmacokinetics of 6-OH-buspirone in rats, 2) to characterize the in vivo potency of 6-OH-buspirone and buspirone at the 5-HT_1A receptor by measuring receptor occupancy using in vivo autoradiography, and 3) to investigate the requirement of 5-HT_1A occupancy for buspirone at behaviorally active doses.

	Materials and Methods

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Pharmacokinetic Studies in Rats. Male Sprague-Dawley rats (weighing 250–350 g) (Charles River, Wilmington, MA) with single carotid artery catheterization were used in this study. Rats (n = 3/dose group) received either a single 5 mg/kg i.a. dose or a single 10 mg/kg p.o. dose of 6-OH-buspirone or buspirone. The vehicle for both the i.a. and p.o. dosing was 0.2 M sodium acetate buffer, pH 4. Serial blood samples (0.25 ml) were collected at predose and 0.1, 0.2, 0.25, 0.5, 1, 2, 4, 6, 8, and 12 h after i.a. dosing and at predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8 and 12 h after p.o. dosing. Immediately upon collection, the blood was mixed with K₃EDTA and stored on ice. Within 60 min, blood samples were centrifuged at approximately 1000g for 15 min at 4°C, and plasma was harvested. The plasma samples were stored at –70°C until use.

Concentrations of buspirone, 6-OH-buspirone, and 1-PP in plasma were quantitated using a liquid chromatography tandem mass spectrometry (LC/MS/MS) method. Briefly, 50 µl of plasma, 50 µl of 10 ng/ml internal standard solution, and 0.2 ml of phosphate-buffered saline were mixed. Samples were passed through a conditioned C₁₈ (EC) solid phase extraction cartridge, washed with 1 ml of water and 0.5 ml of 50:50 (v/v) methanol/water, and eluted with approximately 2 ml of 3% ammonium hydroxide in acetonitrile. The eluted sample was transferred and evaporated to dryness under nitrogen at 40°C. Residues were reconstituted with 0.1 ml of 10:1 (v/v) 100 mM ammonium acetate/ethanol, and 10 µl was analyzed using LC/MS/MS. High-performance liquid chromatography separation was achieved using a mobile phase consisting of 50% A [aqueous 5 mM ammonium acetate (0.1% formic acid)] and 50% B [90:10 methanol/water 5 mM ammonium acetate (0.1% formic acid)] on a Betasil-C₁₈ column (2 x 100 mm, 5 µm) (Thermo Electron Corporation, Waltham, MA) at a flow rate of 250 µl/min with an analysis time of 4 min. Detection was performed in positive, multiple reaction monitoring mode using a Micromass Quattro liquid chromatograph (Waters, Milford, MA) with an electron ionization source as the LC/MS/MS interface.

In Vivo Autoradiography Studies. Male Sprague-Dawley rats (weighing 250–350 g) with dual jugular vein catheterization (Charles River Laboratories, Wilmington, MA) were used in this study. Rats were housed in polycarbonate cages and maintained on a 12:12 h light/dark cycle with free access to standard chow and water. Buspirone (Bristol-Myers Squibb, Wallingford, CT), 6-OH-buspirone (Bristol-Myers Squibb), and [³H]WAY-100635 (a selective 5-HT_1A antagonist; GE Healthcare, Chalfont St. Giles, Buckinghamshire, UK) dosing solutions were freshly prepared using sterile saline as vehicle. For buspirone experiments, rats were injected i.v. with a loading dose of buspirone (0.45–12 mg/kg), immediately followed by a continuous infusion of the buspirone at 0.45 to 12 mg/kg/h for 90 min through one jugular vein. For 6-OH-buspirone experiments, rats were injected i.v. with a loading dose of 6-OH-buspirone (2.4–23.7 mg/kg), immediately followed by a continuous infusion of 6-OH-buspirone at 2.4 to 23.7 mg/kg/h for 90 min through one jugular vein. For both groups of rats, blood samples (0.3–0.4 ml) were taken at 0, 40, 50, and 60 min postdose through the second jugular vein. In previous pilot experiments, it was determined that steady-state plasma concentrations of buspirone and 6-OH-buspirone were achieved by 40 min after the start of the infusion under the protocol described (data not shown). Steady-state plasma concentrations (C_ss) of buspirone and 6-OH-buspirone are presented as the mean ± S.D. of the 40-, 50-, and 60-min time points.

Immediately after the last blood sample, 10 µCi/100 g b.wt. [³H]WAY-100635 (in 0.6–0.7 ml of saline) was injected i.v. Rats were decapitated 30 min later, the brains were collected, frozen, and sectioned (20 µm) using a Cryostat, and sections were mounted on Superfrost slides (VWR, Wilmington, DE). Brain sections were exposed to tritium-sensitive phosphor screens (PerkinElmer Life and Analytical Sciences, Shelton, CT) for 2 to 3 weeks, and images of [³H]WAY-100635 binding in the brain were captured and analyzed using a Cyclone Storage Phosphor Imaging System (PerkinElmer Life and Analytical Sciences). The cerebellum, where 5-HT_1A receptor density is nominal, was used as a reference region for defining nonspecific binding. The percentage occupancy at 5-HT_1A receptors in the region of interest was calculated as 100% – percent ([³H]WAY-100635 binding in drug-treated – [³H]WAY-100635 binding in cerebellum)/([³H]WAY-100635 binding in vehicle [[³H]WAY-100635 binding in cerebellum).

Concentrations of buspirone and 6-OH-buspirone in the plasma were quantitated using a LC/MS/MS method. Briefly, 0.1 ml of plasma, 50 µl of 200 nM internal standard solution, and 0.1 ml of 0.1 M Na₂CO₃ were mixed followed by the addition of 1.0 ml of 1:1 methyl tert-butyl ether /ethyl acetate. Samples were vortexed and centrifuged, and the organic layer was transferred and evaporated to dryness under nitrogen at 60°C. Residues were reconstituted with 0.1 ml of H₂O/CH₃CN/HCOOH (50:50:0.1, v/v/v). High-performance liquid chromatography separation was achieved using an acetonitrile (0.1% formic acid)/water (0.1% formic acid) gradient on a Zorbax SB-C₁₈ column (2 x 50 mm, 5 µm) (Agilent Technologies, Palo Alto, CA) at a flow rate of 200 µl/min with an analysis time of 5 min. Detection was performed in positive, multiple resolution mode using a Micromass Quattro Ultima mass spectrometer (Waters) with an electron ionization source as the LC/MS/MS interface.

Data Analysis. Plots of 5HT_1A receptor occupancy versus plasma concentration were fitted to a one-site binding model using nonlinear regression according to the following equation: % occupancy = B_max x C/(EC₅₀ + C), where B_max is the maximal binding, C is the drug concentration, and EC₅₀ is the concentration required for 50% receptor occupancy. Nonlinear regression was performed using GraphPad Prism (version 3.00; GraphPad Software, San Diego, CA). Estimates of EC₅₀ are reported as the estimate ± S.E.

All pharmacokinetic parameters were calculated by noncompartmental methods as described by Gibaldi and Perrier (1982). Pharmacokinetic parameters [aside from the time at which C_max is observed (t_max)] are reported as the mean ± S.D. t_max is presented as the median along with the observed range in parentheses.

	Results

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The pharmacokinetic parameters of 6-OH-buspirone and buspirone in rats are summarized in Table 1. Plasma clearances for both buspirone and 6-OH-buspirone were high in relation to liver blood flow in rats, being 68.7 ± 8.7 and 47.3 ± 3.5 ml/min/kg, respectively (Table 1). Estimates of volume of distribution at steady-state (V_ss), and half-life (t_1/2) were also were comparable. 6-OH-buspirone had greater exposure after oral administration than buspirone with higher estimates of both bioavailability and the maximum observed concentration achieved after oral dosing (C_max). (Table 1). Figure 2 shows plasma concentration-time profiles of buspirone, 6-OH-buspirone, and 1-PP in rats after a single 5 mg/kg i.a. or 10 mg/kg p.o. dose of buspirone. Plasma concentrations of both 6-OH-buspirone and 1-PP were noticeably higher than those of the parent compound when buspirone was administered orally. Mean area under the concentration-time profile (AUC) estimates for the buspirone metabolites were approximately 12 (6-OH-buspirone)- and 48 (1-PP)-fold higher than AUC estimates for the parent compound after oral dosing (Fig. 2; Table 2).

View larger version (19K): [in this window] [in a new window]   FIG. 2. Plasma concentration-time profile of buspirone and its metabolites, 6-OH-buspirone and 1-PP, after i.a. (5 mg/kg) (A) and p.o. (10 mg/kg) (B) administration of buspirone.

The distribution pattern of 5-HT_1A receptors labeled by intravenous injections of [³H]WAY-100635 in the rat brain is consistent with that reported previously (Hume et al., 1994; Khawaja, 1995). A high density of [³H]WAY-100635 binding appeared in the cortex, septum, hippocampus, hypothalamus, and raphe nuclei in the brainstem. An intravenous infusion of buspirone or 6-OH-buspirone inhibited [³H]WAY-100635 in all these regions in a dose-dependent manner. Figure 3 shows representative autoradiograms of the inhibitory effect of 6-OH-buspirone on in vivo [³H]WAY-100635 binding in the forebrain areas including the hippocampus from rats receiving various doses of 6-OH-buspirone (Fig. 3, A–C).

View larger version (68K): [in this window] [in a new window]   FIG. 3. Inhibition of [3H]WAY-100635 binding in rat brain after intravenous infusions of 6-OH-buspirone at various infusion rates. A, vehicle; B, 2.4 mg/kg/h; C, 11.9 mg/kg/h. Hip, hippocampus. Scale bar, 2 mm.

In Fig. 4 the relationship between brain 5-HT_1A receptor occupancy in hippocampus and dorsal raphe and plasma concentrations of buspirone and 6-OH-buspirone is examined. The data for each brain region were fitted to a one-site binding model, and the estimated in vivo EC₅₀ values are presented in Table 5. The in vivo affinity of buspirone (or its metabolites) appeared more potent for 5-HT_1A receptors in the dorsal raphe than in the hippocampus (Table 5; Fig. 4). Likewise, 6-OH-buspirone exhibited a higher in vivo affinity in the dorsal raphe than in the hippocampus.

View larger version (16K): [in this window] [in a new window]   FIG. 4. Relationship between 5-HT1A receptor occupancy in two brain regions (hippocampus and dorsal raphe) and plasma concentration after intravenous infusions of buspirone (A) and 6-OH-buspirone (B).

	Discussion

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The clearance of buspirone in rats estimated from the current study is similar to the clearance estimate of 51 ml/min/kg observed by Caccia et al. (1983). 6-OH-buspirone showed pharmacokinetics similar to buspirone in rats with the exception of mean oral bioavailability, which was 13-fold higher (Table 1). A recent pharmacokinetic study in humans reported a similar range of half-lives for both buspirone (2.8–4.6 h) and 6-OH-buspirone (4.7–4.3 h) after oral administration of buspirone, which is consistent with similar elimination characteristics of both compounds in humans (Dockens et al., 2006). Currently, there is no literature information on the oral bioavailability of 6-OH-buspirone in humans.

The in vivo affinity/potency of buspirone and 6-OH-buspirone at 5-HT_1A receptors in the brain was examined after intravenous infusions of both compounds to steady state in the rat. In vivo binding of [³H]WAY-100635, a selective 5-HT_1A antagonist, in the hippocampus and dorsal raphe was dose dependently inhibited by buspirone and 6-OH-buspirone, indicating their interaction with 5-HT_1A receptors in vivo. The in vivo affinity at 5-HT_1A receptors for both compounds was 3- to 4-fold higher in the dorsal raphe than in the hippocampus (Table 5). As elucidated in the Introduction, the forebrain regions including the hippocampus express postsynaptic 5-HT_1A receptors, whereas the dorsal raphe posses 5-HT_1A somatodendritic autoreceptors. A higher affinity to the autoreceptors relative to that for the postsynaptic receptors has been observed with pindolol, a ß-adreno-receptor antagonist with a high 5-HT_1A affinity, and been postulated to underlie the effect of pindolol for augmentation of the selective serotonin reuptake inhibitor antidepressant efficacy (Raurich et al., 1999; Rabiner et al., 2000; Martinez et al., 2001). The dorsal raphe has also been considered to play an important role in the anxiolytic effects of 5-HT_1A partial agonists, including buspirone, whose effects have been hypothesized to be mediated by desensitizing 5-HT_1A autoreceptors in the dorsal raphe (Sim-Selley et al., 2000). Our observation of a higher affinity binding of buspirone and its major metabolite, 6-OH-buspirone, to 5-HT_1A autoreceptors in the dorsal raphe supports the hypothesis.

Although 6-OH-buspirone was present in the plasma after buspirone infusions, the levels of the metabolite were 6- to 20-fold less than that of the parent compound. As the in vivo affinity of 6-OH-buspirone at the 5-HT_1A receptor is comparable to that of buspirone (Table 5), the contribution of this metabolite in occupying 5-HT_1A receptors in the buspirone experiments is probably low. Although 1-PP was not quantitated in this experiment, it has been shown to have low in vitro affinity and selectivity at 5-HT₁ receptors in rat brain (Caccia et al., 1986; Gobbi et al., 1991) and thus is not likely to contribute significantly to the 5-HT_1A occupancy observed in our studies.

To our knowledge, this is the first published report on the activity of 6-OH-buspirone at the 5-HT_1A receptor. On the basis of the current study, the in vivo affinity/potency of 6-OH-buspirone appears to be comparable to that of buspirone. Buspirone has been shown to have extensive hepatic first-pass metabolism in both rats and humans with a reported bioavailability of 4% in humans (Caccia et al., 1983; Mahmood and Sahajwalla, 1999). Although we observed relatively low levels of 6-OH-buspirone compared with those of buspirone after intravenous infusions (Table 3) and intra-arterial dosing (Table 2) of the parent compound, it could contribute significantly to the biological activity of buspirone after oral dosing due to the higher circulating levels of metabolites resulting from extensive first-pass metabolism. The current pharmacokinetic study in rats shows oral exposures of 6-OH-buspirone that are 12-fold higher than those of buspirone after a 10 mg/kg p.o. buspirone dose (Fig. 2; Table 2). In humans, oral exposures of 6-OH-buspirone are even higher, being 40 fold greater than those for buspirone when oral doses of buspirone over the therapeutic dose range (10–60 mg daily) are given (Dockens et al., 2006).

Receptor occupancy requirements associated with an anxiolytic effect at the 5-HT_1A receptor is not well understood. In both the fear-induced and air-puff-elicited ultrasonic vocalization models of anxiety in rats, buspirone has been shown to have anxiolytic effects at an oral dose of 10 mg/kg (Vis et al., 2001; Naito et al., 2003). Based on concentrations of buspirone and 6-OH-buspirone observed in the current study and in vivo EC₅₀ estimates presented in Table 5, maximum 5-HT_1A receptor occupancies of 23% in the dorsal raphe and 7% in the hippocampus occur after an oral dose of 10 mg/kg to rats. In a recent study in humans, buspirone and 6-OH-buspirone concentrations were monitored after 5 days of buspirone administration over the therapeutic dose range (Dockens et al., 2006). At the highest dose used in the study (i.e., oral doses of 30 mg/kg twice daily), mean C_max values of 2.0 ng/ml (0.005 µM) and 39 ng/ml (0.097 µM) were reported for buspirone and 6-OH-buspirone, respectively. These concentrations would result in 5-HT_1A receptor occupancies of 10% in the dorsal raphe and 3% in the hippocampus using in vivo EC₅₀ estimates presented in Table 5.

Low levels of 5-HT_1A receptor occupancy by buspirone at clinically effective doses have been reported previously in human positron emission tomography studies (Rabiner et al., 2000; Passchier et al., 2001). A single dose of 10 or 40 mg of buspirone occupies 5% 5-HT_1A receptors in healthy human subjects (Rabiner et al., 2000; Passchier et al., 2001). A similar low fraction (<10%) of occupancy in humans has been observed with other selective and nonselective 5-HT_1A agonists such as tandospirone, flesinoxan, and EMD 128 130 after single or multiple clinical doses capable of activating central 5-HT_1A receptor functions (Nakayama et al., 2002; Rabiner et al., 2002; Bantick et al., 2004). Results of the current study are consistent with these literature observations, suggesting that high levels of 5-HT_1A receptor occupancy are not required to elicit an anxiolytic effect either preclinically in rats and clinically in humans.

In summary, the present study demonstrates that 6-OH-buspirone is the major active metabolite of buspirone with similar in vivo potency at the 5-HT_1A receptor. 6-OH-buspirone has improved oral exposure in comparison with buspirone and could be an effective anxiolytic agent alternative to buspirone. Finally, results of our current study are consistent with literature reports suggesting that a low 5-HT_1A receptor occupancy requirement is needed for anxiolytic activity.

	Acknowledgments

 
We thank our colleagues Vincenzo Calandra, Xiao-Xin Yan, Todd Strong, Shelly X. Ren, and Rick Pieschl for contributing to this study.

	Footnotes

 
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

doi:10.1124/dmd.107.015768.

ABBREVIATIONS: 5HT, 5-hydroxytryptamine; OH, hydroxy; 1-PP, 1-(2-pyrimidinyl)-piperazine; LC/MS/MS, liquid chromatography-tandem mass spectrometry; WAY-100635, [O-methyl-3H]-N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride; AUC, area under the plasma-concentration time profile; EMD 128 130, sarizotan.

¹ Current affiliation: Genentech, Inc., South San Francisco, California.

² Current affiliation: Roche Pharmaceuticals, Nutley, New Jersey.

³ Current affiliation: AstraZeneca Pharmaceuticals, Wilmington, Delaware.

Address correspondence to: Dr. Yu-Wen Li, Neuroscience Biology, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492-7660. E-mail: yu-wen.li{at}bms.com

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This Article Abstract Full Text (PDF) All Versions of this Article: dmd.107.015768v1 35/8/1387    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wong, H. Articles by Li, Y.-W. Search for Related Content PubMed PubMed Citation Articles by Wong, H. Articles by Li, Y.-W.