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

Abstract

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

Physiologically Based Pharmacokinetic Modeling of Intestinal First-Pass Metabolism of CYP3A Substrates with High Intestinal Extraction

“…). The metabolism of buspirone has been suggested to be mainly mediated by CYP3A and a similar metabolite pattern in HLM was reported in comparison with that in vivo (Jajoo et al, 1989;Zhu et al, 2005). Previously reported metabolite formation data resulted in marginally higher CLu int values (correction for fu inc applied) compared with our substrate depletion data (460 versus 268 l ⅐ min Ϫ1 ⅐ mg Ϫ1 ) (Zhu et al, 2005;Gertz et al, 2010).…”

Microsomal Cytochrome P450-Mediated Metabolism of Protopanaxatriol Ginsenosides: Metabolite Profile, Reaction Phenotyping, and Structure-Metabolism Relationship

“…In this study, it has been found that the typical PPT ginsenoside turnover rate in CYP3A4 was much higher (ranging from 12-to 48-fold) than that in CYP3A5, suggesting that CYP3A4 should be the predominant isoform and that CYP3A5 contributed very little to the oxygenation metabolism of ginsenosides. Such a phenomenon has been also widely found for many other typical CYP3A substrates such as buspirone (Zhu et al, 2005) and cyclosporin A.…”

Biotransformation of 3-Amino-5,6,7,8-tetrahydro-2-{4-[4-(quinolin-2-yl)piperazin-1-yl]butyl}quinazolin-4(3H)-one (TZB-30878), a Novel 5-Hydroxytryptamine (5-HT)1A Agonist/5-HT3 Antagonist, in Human Hepatic Cytochrome P450 Enzymes

“…The fragment ion was shown at m/z 218, suggesting that M6 had a hydroxy group that could be dehydrated. It is known that breaking of the C-N bond between an alkyl group and piperazine ring can occur (Zhu et al, 2005). Our findings suggested that M6 might be a cyclic form arising via cyclization of the aldehyde form (Thompson et al, 1996(Thompson et al, , 2000Singh et al, 2003).…”