CYTOCHROME P450 3A-MEDIATED METABOLISM OF BUSPIRONE IN HUMAN LIVER MICROSOMES

@article{Zhu2005CYTOCHROMEP3,
  title={CYTOCHROME P450 3A-MEDIATED METABOLISM OF BUSPIRONE IN HUMAN LIVER MICROSOMES},
  author={Mingshe Zhu and Weiping Zhao and Humberto Jimenez and Donglu Zhang and Suresh N. Yeola and Renke Dai and Nimish N. Vachharajani and James G Mitroka},
  journal={Drug Metabolism and Disposition},
  year={2005},
  volume={33},
  pages={500 - 507}
}
This study was carried out to determine the metabolic pathways of buspirone and cytochrome P450 (P450) isoform(s) responsible for buspirone metabolism in human liver microsomes (HLMs). Buspirone mainly underwent N-dealkylation to 1-pyrimidinylpiperazine (1-PP), N-oxidation on the piperazine ring to buspirone N-oxide (Bu N-oxide), and hydroxylation to 3′-hydroxybuspirone (3′-OH-Bu), 5-hydroxybuspirone (5-OH-Bu), and 6′-hydroxybuspirone (6′-OH-Bu) in HLMs. The apparent Km values for buspirone… 

Figures and Tables from this paper

Identification of CYP3A4 as the primary cytochrome P450 responsible for the metabolism of tandospirone by human liver microsomes

The results indicate that the metabolism of tandospirone by human liver microsomes primarily involves CYP3A4, and to a lesser extent CYP2D6.

Comparison of the Contributions of Cytochromes P450 3A4 and 3A5 in Drug Oxidation Rates and Substrate Inhibition

The collective findings give insight into the contribution of polymorphic P450 3A5 to drug metabolism and adverse drug interactions.

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

Results obtained from this study suggest that CYP3A4-catalyzed oxygenation metabolism plays an important role in the hepatic disposition of ginsenosides and that glycosyl substitution, especially at the C20 hydroxy group, determines their intrinsic clearances by CYP 3A4.

6-Hydroxybuspirone Is a Major Active Metabolite of Buspirone: Assessment of Pharmacokinetics and 5-Hydroxytryptamine1A Receptor Occupancy in Rats

Preclinical data suggest that 6-OH-buspirone probably contributes to the clinical efficacy of buspirone as an anxiolytic agent.

Inhibition of Axitinib on Buspirone Metabolism in vitro and in vivo

Axitinib inhibited buspir one metabolism in vivo and in vitro, which increases the risk of the side effects of buspirone in the clinic, and when coadministered with axitinib, a lower dosage of busPirone should be defined to avoid a toxic response.

Differential regulation of intestinal and hepatic CYP3A by 1α,25‐dihydroxyvitamin D3: Effects on in vivo oral absorption and disposition of buspirone in rats

This study provides the first reported data regarding the effects of 1,25(OH)2D3 treatment on the in vivo pharmacokinetics of intravenous and oral buspirone in rats, by the differential modulation of hepatic and intestinal CYP3A activity.

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

In vitro experiments in human liver microsomes with cytochrome P450 (P450)-specific inhibitors revealed that CYP3A4 was the major enzyme responsible for the metabolism of TZB-30878, a novel 5-hydroxytryptamine ( 5-HT)1A agonist/5-HT3 antagonist under development for the treatment of irritable bowel syndrome.

Effect of blueberry juice on clearance of buspirone and flurbiprofen in human volunteers.

The studies provide no evidence for concern about clinically important pharmacokinetic drug interactions of BBJ with substrate drugs metabolized by CYP3A or CYP2C9 and BBJ has no effect on flurbiprofen AUC.

Effects of cytochrome P450 (CYP) 3A4 inhibitors on the anxiolytic action of tandospirone in rat contextual conditioned fear

...

References

SHOWING 1-10 OF 34 REFERENCES

In vitro metabolism of the antianxiety drug buspirone as a predictor of its metabolism in vivo.

Hepatocytes and phenobarbital- induced rat liver microsomes were better predictors of in vivo metabolism of buspirone than non-induced rat livermicrosomes and these in vitro systems should provide excellent models for studying the metabolism of other azaspirodecanedione-containing drugs.

Metabolism of the antianxiety drug buspirone in the rat.

Seven major metabolites of the antianxiety drug buspirone were unambiguously identified together with unchanged drug and accounted for greater than 90% of the total metabolites excreted in the rat bile and urine samples.

Metabolism of the antianxiety drug buspirone in human subjects.

The metabolism of an oral dose of the antianxiety drug buspirone labeled with 14C/15N was studied in human subjects to facilitate structural characterization of the metabolites by mass spectrometry.

Disposition and metabolism of buspirone and its metabolite 1-(2-pyrimidinyl)-piperazine in the rat.

The metabolite 1-(2-pyrimidinyl)-piperazine (1-PP) has a longer t1/2 than buspirone and may contribute to the pharmacological effect of the parent drug.

Human cytochromes mediating gepirone biotransformation at low substrate concentrations

Biotransformation of gepirone to 1‐(2‐pyrimidinyl)‐piperazine (1‐PP) and 3'‐OH‐gepirone, as well as two other hydroxylated metabolites, was studied in vitro using a human liver microsomal preparation

Metabolism and disposition of buspirone.

Interactions of buspirone with itraconazole and rifampicin: effects on the pharmacokinetics of the active 1-(2-pyrimidinyl)-piperazine metabolite of buspirone.

Itraconazole and rifampicin caused only relatively minor changes in the plasma concentrations of the active piperazine metabolite of buspir one, although they had drastic effects on the concentrations of parent buspirone.

(+)-N-3-Benzyl-nirvanol and (-)-N-3-benzyl-phenobarbital: new potent and selective in vitro inhibitors of CYP2C19.

In conclusion, N-3-benzyl derivatives of nirvanol and phenobarbital represent new, highly potent and selective inhibitors of CYP2C19 that are likely to prove generally useful for screening purposes during early phases of drug metabolism studies with new chemical entities.

Clinical Pharmacokinetics and Pharmacodynamics of Buspirone, an Anxiolytic Drug

The mechanism of action of the drug is not well characterised, but it may exert its effect by acting on the dopaminergic system in the central nervous system or by binding to serotonin (5-hydroxytryptamine) receptors.

Effect of the novel anxiolytic drug deramciclane on the pharmacokinetics and pharmacodynamics of the CYP3A4 probe drug buspirone

Deramciclane does not inhibit CYP3A4 activity as measured by buspirone pharmacokinetics, and there were no indications of relevant pharmacodynamic interaction after multiple doses of deramcIClane and a single dose of buspir one.