Plasma buspirone concentrations are greatly increased by erythromycin and itraconazole*

Kivistö, Kari T.; Lamberg, Tommi; Kantola, Taru; Neuvonen, Pertti J.

doi:10.1016/s0009-9236(97)90038-2

Cited by 126 publications

(76 citation statements)

References 20 publications

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“…Furthermore, the metabolism of buspirone in a panel of human liver microsomes correlated well with enzyme activity only for CYP3A, among eight P450 isoforms tested (Table 3). Finally, the in vitro P450 reaction phenotyping data are in agreement with the in vivo observations that CYP3A4 inhibitors verapamil, diltiazem, (Lamberg et al, 1998a), erythromycin, itraconazole (Kivisto et al, 1997), and grapefruit juice (Lilja et al,1998) substantially increase the AUC and C max of buspirone. In contrast, the CYP3A4 inducer rifampicin significantly decreases the AUC and C max of buspirone (Lamberg et al, 1998b;Kivisto et al, 1999).…”

Section: Discussionsupporting

confidence: 84%

“…Results from these studies demonstrate that CYP3A inhibitors, verapamil, diltiazem, erythromycin, itraconazole, and grapefruit juice, substantially increase the area under the curve (AUC) and the maximum concentration (C max ) of buspirone in human plasma, presumably by inhibiting CYP3A-mediated metabolic clearance (Kivisto et al, 1997;Lamberg et al, 1998a;Lilja et al, 1998). In addition, a CYP3A inducer, rifampicin, decreases the AUC and C max of buspirone in human plasma by 90 and 84%, respectively (Lamberg et al, 1998b;Kivisto et al, 1999).…”

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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: Discussionsupporting

confidence: 84%

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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“…at ASPET Journals on May 10, 2018 dmd.aspetjournals.org consistent with the in vivo observations on the marked increases in buspirone plasma concentrations in humans pretreated with selective P4503A4 inhibitors including grapefruit juice, erythromycin, and itraconazole (Kivisto et al, 1997;Lilja et al, 1998).…”

Section: Nefazodone Bioactivation To Reactive Metabolitessupporting

confidence: 89%

“…It is noteworthy to point out that, like nefazodone, the antianxiety drug (8-[4-[4-(2-pyrimidinyl)-piperazinyl]butyl-8-azaspiro [4,5]-decane-7,9-dione (buspirone) also undergoes a P450 3A4-catalyzed aromatic hydroxylation that occurs para to the piperazinyl nitrogen leading to p-hydroxybuspirone (metabolite 5) ( Fig. 1) (Gammans et al, 1986;Jajoo et al, 1989;Kivisto et al, 1997). Furthermore, buspirone-N-dealkylation generates the corresponding 1-(2-pyrimidinyl)piperazine (1-PP) metabolite (Mayol et al, 1985;Caccia et al, 1986), which upon further oxidation furnishes p-hydroxy-1-PP (metabolite 6) ( Fig.…”

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confidence: 99%

Bioactivation of the Nontricyclic Antidepressant Nefazodone to a Reactive Quinone-Imine Species in Human Liver Microsomes and Recombinant Cytochrome P450 3a4

Kalgutkar¹,

Vaz²,

Lame³

et al. 2004

Drug Metab Dispos

150

116

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ABSTRACT:The therapeutic benefits of the antidepressant nefazodone have been hampered by several cases of acute hepatotoxicity/liver failure. Although the mechanism of hepatotoxicity remains unknown, it is possible that reactive metabolites of nefazodone play a causative role. Studies were initiated to determine whether nefazodone undergoes bioactivation in human liver microsomes to electrophilic intermediates. Following incubation of nefazodone with microsomes or recombinant P4503A4 in the presence of sulfydryl nucleophiles, conjugates derived from the addition of thiol to a monohydroxylated nefazodone metabolite were observed. Product ion spectra suggested that hydroxylation and sulfydryl conjugation occurred on the 3-chlorophenylpiperazine-ring, consistent with a bioactivation pathway involving initial formation of p-hydroxynefazodone, followed by its two-electron oxidation to the reactive quinone-imine intermediate. The formation of novel N-dearylated nefazodone metabolites was also discernible in these incubations, and 2-chloro-1,4-benzoquinone, a by-product of N-dearylation, was trapped with glutathione to afford the corresponding hydroquinone-sulfydryl adduct. Nefazodone also displayed NADPH-, time-, and concentration-dependent inactivation of P4503A4 activity, suggesting that reactive metabolites derived from nefazodone bioactivation are capable of covalently modifying P4503A4. A causative role for 2-chloro-1,4-benzoquinone and/or the quinone-imine intermediate(s) in nefazodone hepatotoxicity is speculated. Although the antianxiety agent buspirone, which contains a pyrimidine ring in place of the 3-chlorophenyl-ring, also generated phydroxybuspirone in liver microsomes, no sulfydryl conjugates of this metabolite were observed. This finding is consistent with the proposal that two-electron oxidation of p-hydroxybuspirone to the corresponding quinone-imine is less favorable due to differences in the protonation state at physiological pH and due to weaker resonance stabilization of the oxidation products as predicted from ab initio measurements.

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“…erythromycin was catalogued as a strong inhibitor of CYP3A based on its interaction with buspirone rather than with midazolam [22,23]). The …”

Section: A նTwofold Change In the Clearance Of In Vivomentioning

confidence: 99%

Perpetrators of pharmacokinetic drug–drug interactions arising from altered cytochrome P450 activity: a criteria‐based assessment

Polasek

Lin

Miners

et al. 2011

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Many drugs inhibit or induce cytochrome P450 enzymes (CYP) to cause clinically significant changes in the concentrations of other drugs, i.e.'perpetrate' pharmacokinetic drug-drug interactions (PK-DDIs).• Tables that list the substrates, inhibitors and inducers of CYP are common, but they lack consistency and are constructed from evidence of variable quality. WHAT THIS STUDY ADDS• This is the first study to catalogue important perpetrators of PK-DDIs using objective criteria and clinical pharmacokinetic drug interaction studies. This information is intended to inform clinical decisions on PK-DDIs.• Existing tables of CYP inhibitors and inducers have low sensitivity and low positive predictive value in identifying the major perpetrators of PK-DDIs. • Several drugs were identified which potentially perpetrate CYP-mediated PK-DDIs, but quality clinical pharmacokinetic interaction studies are lacking. This information may be used to inform future research. AIMSTo catalogue the perpetrators of CYP-mediated pharmacokinetic drug-drug interactions (PK-DDIs) using clinically relevant criteria, and to compare this with an analogous catalogue. METHODSCandidate inhibitors and inducers of CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A ('perpetrators') were evaluated using published clinical pharmacokinetic interaction studies. Studies were selected on the basis of Նsix human subjects, use of a validated in vivo probe substrate for the CYP enzyme, and clinically relevant dosing. Inhibitors were described according to the FDA classifications of strong, moderate or weak, whereas inducers were classified as major (Նtwofold decrease in AUC) or weak (

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Plasma buspirone concentrations are greatly increased by erythromycin and itraconazole*

Cited by 126 publications

References 20 publications

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

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

Bioactivation of the Nontricyclic Antidepressant Nefazodone to a Reactive Quinone-Imine Species in Human Liver Microsomes and Recombinant Cytochrome P450 3a4

Perpetrators of pharmacokinetic drug–drug interactions arising from altered cytochrome P450 activity: a criteria‐based assessment

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