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
