Buspirone metabolite structure profile using a standard liquid chromatographic-mass spectrometric protocol

Kerns, Edward H.; Rourick, Robyn A.; Volk, Kevin J.; Lee, Mike S.

doi:10.1016/s0378-4347(97)00254-5

Cited by 68 publications

(59 citation statements)

References 17 publications

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“…A similar MS/MS fragmentation pattern of buspirone under ionspray ionization conditions was previously reported (Kerns et al, 1997 dmd.aspetjournals.org LC/MS/MS. LC/MS/MS analysis was carried out for metabolite identification by using the Shimadzu HPLC system (described above) coupled with a Finnigan TSQ quantum triple quadrupole mass spectrometer (Thermo Finnigan, San Jose, CA).…”

Section: Ms Fragments and Their Interpretation Of Buspirone Metabolitsupporting

confidence: 82%

“…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).…”

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confidence: 99%

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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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Section: Ms Fragments and Their Interpretation Of Buspirone Metabolitsupporting

confidence: 82%

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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“…Firstly, it provides a reference-friendly format to search data and this feature is essential for the rapid identification of known compounds. For example, the identification of a metabolite structure may require only a retention time and molecular weight information via LC-MS analysis when compared to the metabolite structure database compiled from previous studies [10]. A second benefit of databases is the efficient extraction of information.…”

Section: Desktop Data Analysis and Tools For Ms Spectrometristsmentioning

confidence: 99%

Applications of Computer Software for the Interpretation and Management of Mass Spectrometry Data in Pharmaceutical Science

Williams¹

2002

CTMC

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Abstract:The rapid growth of mass spectrometry (MS)-based computer software applications has been fueled by the unprecedented need to capture and analyze MS data and provide the information necessary for decision-making. Shorter timelines and a significantly greater number of samples has resulted in a tremendous focus on streamlined approaches that provide scientists, managers, and executives the capability to readily obtain, or even request, the necessary information that leads to accelerated product development. The generation of analytical data using roboticized high-throughput hardware has produced a bottleneck since data can be generated faster than it can be analyzed. New techniques including MS/MS and accurate mass experiments are feasible only using computers to capture and manage the enormous amounts of data necessary to perform the experiments. Whatever the nature of the experiments conducted, the MS analysis strategy is to extract the appropriate information required for decision-making in as facile a manner as possible. We will review here a survey of the creation of commercial and laboratory specific reference databases and associated searching algorithms and also recent efforts to introduce advanced processing and analysis algorithms to the hands of the masses, specifically as an aid to structure elucidation.

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“…The combination of liquid chromatography and mass spectrometry (LC/MS) is the most commonly used approach for low level drug analysis in biofluids. [1][2][3][4][5][6][7][8] Currently, within the pharmaceutical industry, there is a need for higher throughput, higher sensitivity assays and reduced method development time. There are two main driving forces behind these needs.…”

mentioning

confidence: 99%

“…The mass spectrometers used for such assays rely on atmospheric pressure ionisation (API), typically pneumatically assisted electrospray, and are operated in tandem MS mode, producing a high level of specificity. [2][3][4] Several approaches, such as 96 well SPE, 9 direct on-column analysis 10 and column-switching, 7 have been tried in order to increase analytical throughput with various degrees of success. The use of fast generic gradient HPLC has been described by Mutton for the rapid screening of candidate drug molecules in the support of combinatorial chemistry.…”

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confidence: 99%

The application of fast gradient capillary liquid chromatography/mass spectrometry to the analysis of pharmaceuticals in biofluids

Plumb¹,

Dear²,

Mallett³

et al. 1999

Rapid Commun. Mass Spectrom.

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Fast gradient capillary high performance liquid chromatography (HPLC) coupled to a mass spectrometer has been successfully used for the analysis of pharmaceutical compounds from biological matrices, in the femtogram on column range. In the work reported in this paper, the use of capillary HPLC, on the 180-micron internal diameter scale, has shown a 30-fold improvement in detection limits when compared to conventional 2-mm scale chromatography. The use of fast gradient elution resulted in a generic methodology which gave excellent chromatographic reproducibility and column longevity. This technique has been used in conjunction with simple protein precipitation, with no deleterious effect on either the column life or the chromatographic performance. The use of capillary HPLC in bioanalysis has the potential to give a significant increase in assay sensitivity with the equipment currently in use. In this paper the authors also present a modification to the current PE-Sciex ion-spray source which allows excellent spray adjustment in three dimensional accessibility, which is important when working with low flow rates, as well as reducing the inherent system dead volume.

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Buspirone metabolite structure profile using a standard liquid chromatographic-mass spectrometric protocol

Cited by 68 publications

References 17 publications

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

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

Applications of Computer Software for the Interpretation and Management of Mass Spectrometry Data in Pharmaceutical Science

The application of fast gradient capillary liquid chromatography/mass spectrometry to the analysis of pharmaceuticals in biofluids

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