<i>In vitro</i>metabolism of the antianxiety drug buspirone as a predictor of its metabolism<i>in vivo</i>

Jajoo, Hemant K.; Blair, Ian A.; Klunk, Lewis J.; Mayol, Robert F.

doi:10.3109/00498259009046892

Cited by 30 publications

(30 citation statements)

References 15 publications

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“…These data suggest that N-dealkylation to form 1-PP and hydroxylation to form multiple monohydroxylated metabolites are the primary metabolic pathways responsible for buspirone clearance in humans and rats. In vitro metabolism of buspirone in rats has been investigated in several systems prepared from liver tissues, including S-9 preparation (Kerns et al, 1997), liver slices (Goldthwaite et al, 1996), microsomal preparation, and hepatocytes (Jajoo et at., 1990). Major in vitro metabolic reactions in rats are the formation of 1-PP, 3Ј-OH-Bu, 5-OH-Bu, and 6Ј-OH-Bu, consistent with the in vivo metabolism pathways in rats (Jajoo et al, 1989a).…”

mentioning

confidence: 99%

Cytochrome P450 3a-Mediated Metabolism of Buspirone in Human Liver Microsomes

Zhu¹,

Zhao²,

Jiménez³

et al. 2005

Drug Metab Dispos

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ABSTRACT:This study was carried out to determine the metabolic pathways of buspirone and cytochrome P450 (P450) isoform ( Buspirone is the first marketed anxiolytic drug from the azapirone class of compounds (Fulton and Brogden, 1997). It is as effective as the benzodiazepines for the treatment of anxiety, but buspirone produces fewer adverse side-effects such as sedation, motor impairment, and dependence liability (O'Hanlon, 1991). Unlike benzodiazepine anxiolytics, buspirone has little affinity for the ␥-aminobutyric acidbenzodiazepine complex. Its primary pharmacological action is believed to be associated with the binding to 5-hydroxytryptamine subtype 1A receptor (5-HT 1A ) receptor, resulting in the inhibition of the activity of serotonergic neurons through down-regulation (Goa and Ward, 1986;Fulton and Brogden, 1997). Buspirone, originally approved by the Food and Drug Administration (FDA) for the treatment of generalized anxiety disorder in 1986, has been shown to be efficacious for the treatment of a variety of mental disorders, including panic disorder, major depression, obsessive-compulsive disorder, and social phobia (Fulton and Brogden, 1997;Apter and Allen, 1999;Sramek et al., 2002).Buspirone undergoes extensive first-pass metabolism in humans, resulting in a bioavailability of less than 5%, although it is almost completely absorbed after a single oral administration Gammans et al., 1986). Urinary excretion is the major elimination pathway in humans, accounting for 60% of the total oral dose of [ 14 C]buspirone . 1-Pyrimidinylpiperazine (1-PP), 6Ј-hydroxybuspirone (6Ј-OH-Bu), and multiple secondary metabolites (Fig. 1) are the major drug-related components in the urine, whereas the parent drug only accounts for less than 1% of total urinary radioactivity (Jajoo et al., 1989b). Most of the secondary metabolites in human urine, such as 5-hydroxy-1-pyrimidinylpiperazine (5-OH-1-PP), 5,6Ј-dihydoxybuspirone (5,6Ј-di-OH-Bu), and a ␥-lactone metabolite (Oxa-Bu), are derived from 1-PP, 6Ј-OH-Bu, and 5-OH-Bu. Unchanged buspirone accounts for less than 2% of the total radioactivity) in human plasma (Gammans et al., 1986). Buspirone metabolites, 1-PP, 5-OH-Bu, and a conjugate of 5-OH-Bu, have been found in human plasma (Gammans et al., 1986). However, human plasma metabolite profiles after oral administration of radiolabeled buspirone have not been reported. Buspirone is also extensively metabolized in rats following oral administration (Caccia et al., 1983;Jajoo et al.,1989a). 1-PP, 5-OH-Bu, 6Ј-OH-Bu, 3Ј-OH-Bu, and their further metabolites are found to be the major drug-related components in rat bile and urine. These data suggest that N-dealkylation to form 1-PP and hydroxylation to form multiple monohydroxylated metabolites

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confidence: 99%

Cytochrome P450 3a-Mediated Metabolism of Buspirone in Human Liver Microsomes

Zhu¹,

Zhao²,

Jiménez³

et al. 2005

Drug Metab Dispos

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“…Nefazodone bioactivation by CYP3A4 is also accompanied by mechanism-based inactivation of the isozyme, which is consistent with DDIs between nefazodone and CYP3A4 substrates [67] [68]. As in the case of nefazodone, para-hydroxybuspirone also represents a major circulating metabolite of the anxiolytic agent buspirone (Scheme 7) [69]. However, the failure to detect GSH conjugates in microsomal incubations of buspirone suggests that the drug is not prone to bioactivation [65].…”

Section: Bioactivation Of the Calcium-channel Opener Maxipost In Rat mentioning

confidence: 80%

Structural Alerts, Reactive Metabolites, and Protein Covalent Binding: How Reliable Are These Attributes as Predictors of Drug Toxicity?

Kalgutkar

Didiuk

2009

Chemistry & Biodiversity

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In an increasing number of cases, a deeper understanding of the biochemical basis for idiosyncratic adverse drug reactions (IADRs) has aided to replace a vague perception of a chemical class effect with a sharper picture of individual molecular peculiarity. Considering that IADRs are too complex to duplicate in a test tube, and their idiosyncratic nature precludes prospective clinical studies, it is currently impossible to predict which new drugs will be associated with a significant incidence of toxicity. Because it is now widely appreciated that reactive metabolites, as opposed to the parent molecules from which they are derived, are responsible for the pathogenesis of some IADRs, the propensity of drug candidates to form reactive metabolites is generally considered a liability. Procedures have been implemented to monitor reactive-metabolite formation in discovery with the ultimate goal of eliminating or minimizing the liability via rational structural modification of the problematic chemical series. While such mechanistic studies have provided retrospective insight into the metabolic pathways which lead to reactive metabolite formation with toxic compounds, their ability to accurately predict the IADR potential of new drug candidates has been challenged. There are several instances of drugs that form reactive metabolites, but only a fraction thereof cause toxicity. This review article will outline current approaches to evaluate bioactivation potential of new compounds with particular emphasis on the advantages and limitation of these assays. Plausible reason(s) for the excellent safety record of certain drugs susceptible to bioactivation will also be explored and should provide valuable guidance in the use of reactive-metabolite assessments when nominating drug candidates for development.

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“…Buspirone is extensively metabolized when orally dosed to rats. [24] In addition to the major metabolites included in this study, there are many other oxidative metabolites found in vitro and in vivo. In order to use UV peak area to correct for the mass spectrometry response of one metabolite, it is very important to ensure Table 1) and (B) mass accuracy of internal standard buspirone-D 8 in one analytical run consisting of 99 samples.…”

Section: Quantitative Estimation Of Metabolite Exposure Using Uv Corrmentioning

confidence: 99%

Quantitative estimation of circulating metabolites without synthetic standards by ultra‐high‐performance liquid chromatography/high resolution accurate mass spectrometry in combination with UV correction

Yang

Grubb

Luk

et al. 2011

Rapid Comm Mass Spectrometry

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An early assessment of metabolite exposure in preclinical species can provide quantitative estimation on possible active or toxic metabolites. Frequently, synthetic metabolite standards are not available at the preclinical stage, precluding the quantitation of metabolites by means of calibration curves and quality control (QC) samples. We present here an approach to determine the extent of circulating metabolites using 'metabolite standards' generated by in vitro incubations in combination with the correction for mass spectrometry response based on UV response. The study was done by coupling ultra-high-performance liquid chromatography (UHPLC) to LTQ-Orbitrap high-resolution mass spectrometry, and the quantitation was based on full scan high-resolution accurate mass analysis in combination with retention time. First, we investigated the separation capacity of a 10.5 min UHPLC method and the quantitative capability of an LTQ-Orbitrap for full scan accurate mass quantitation by spiking chemical standards of buspirone and its six metabolites in blank plasma. Then we demonstrated the use of a UV correction approach to quantitatively estimate buspirone and its metabolites in plasma samples from a rat pharmacokinetics study. We compared the concentration versus time profiles of buspirone and its six metabolites in rat plasma samples obtained using three different approaches, including using UV correction, using individual standard curves for each metabolite prepared from the synthetic standard, and using a calibration curve of the parent compound buspirone. We demonstrated the estimated metabolite exposure of buspirone using this UV correction approach resulted in rank ordering of metabolite exposure within three-fold of the value obtained with metabolite standards, in contrast to eight-fold without UV correction. The approach presented in this paper provides a practical solution to an unmet bioanalytical need for quantitative information on metabolites without standards in preclinical in vivo studies.

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In vitrometabolism of the antianxiety drug buspirone as a predictor of its metabolismin vivo

Cited by 30 publications

References 15 publications

Cytochrome P450 3a-Mediated Metabolism of Buspirone in Human Liver Microsomes

Cytochrome P450 3a-Mediated Metabolism of Buspirone in Human Liver Microsomes

Structural Alerts, Reactive Metabolites, and Protein Covalent Binding: How Reliable Are These Attributes as Predictors of Drug Toxicity?

Quantitative estimation of circulating metabolites without synthetic standards by ultra‐high‐performance liquid chromatography/high resolution accurate mass spectrometry in combination with UV correction

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