How is buspirone (anxiolytic medication) metabolized?

Buspirone Metabolism

Buspirone is primarily metabolized in the liver by the cytochrome P450 3A4 (CYP3A4) enzyme system through oxidation, resulting in extensive first-pass metabolism that significantly reduces its bioavailability to approximately 4%. 1, 2

Pharmacokinetic Profile

Absorption and Bioavailability

• Buspirone is rapidly absorbed after oral administration
• Peak plasma concentrations occur within 40-90 minutes after dosing 1
• Absolute bioavailability is low (approximately 4%) due to extensive first-pass metabolism 2
• Food increases bioavailability by decreasing first-pass metabolism:
  • When taken with food, peak plasma concentration (Cmax) increases by 116%
  • Area under the curve (AUC) increases by 84% 1

Distribution

• Volume of distribution: 5.3 L/kg 2
• Protein binding: Approximately 86% bound to plasma proteins 1
• Does not displace highly protein-bound drugs like phenytoin, warfarin, and propranolol 1

Metabolism

• Primary pathway: Oxidation mediated by CYP3A4 1
• Several hydroxylated derivatives are produced 1
• Key active metabolite: 1-pyrimidinylpiperazine (1-PP) 1, 2
  • 1-PP has approximately one-quarter of the anxiolytic activity of buspirone 1
  • 1-PP has a longer half-life (6.1 hours) than parent compound 3
• Metabolism occurs primarily through:
  • Hydroxylation
  • Dealkylation 4

Elimination

• Elimination half-life: 2-3 hours for unchanged buspirone 1
• Excretion:
  • 29-63% excreted in urine within 24 hours (primarily as metabolites)
  • 18-38% excreted in feces 1
• Systemic clearance: Approximately 1.7 L/h/kg 2

Special Populations

Hepatic Impairment

• Steady-state AUC increases 13-fold in patients with hepatic impairment 1
• Half-life doubles in patients with hepatic cirrhosis 5
• Dose adjustment is necessary in hepatic impairment 6

Renal Impairment

• Steady-state AUC increases 4-fold in patients with renal impairment (CrCl 10-70 mL/min/1.73m²) 1
• Modest decrease in buspirone clearance 5
• Not removed by hemodialysis 5

Age and Gender

• No significant differences in pharmacokinetics between elderly and younger subjects 1
• No significant differences between men and women 1

Drug Interactions

CYP3A4 Inhibitors

• Coadministration with CYP3A4 inhibitors can substantially increase buspirone plasma concentrations:
  • Verapamil
  • Diltiazem
  • Erythromycin
  • Itraconazole 2

CYP3A4 Inducers

• Rifampin decreases buspirone plasma concentrations by approximately 10-fold 2
• Other strong CYP3A4 inducers (phenobarbital, carbamazepine, phenytoin) may reduce efficacy and are not recommended 7

Other Interactions

• Aspirin may increase plasma levels of free buspirone by 23% 1
• Flurazepam may decrease plasma levels of free buspirone by 20% 1
• Cimetidine and alprazolam have minimal effects on buspirone pharmacokinetics 2

Clinical Implications

• Buspirone's extensive first-pass metabolism contributes to its variable plasma concentrations between individuals
• Taking buspirone with food significantly increases its bioavailability
• Dose adjustments are necessary for patients with hepatic or renal impairment
• Caution should be exercised when prescribing buspirone with medications that inhibit or induce CYP3A4
• The linear pharmacokinetics over the dose range of 10-40 mg allows for predictable dose adjustments

Understanding buspirone's metabolism is essential for optimizing its therapeutic use, particularly when considering potential drug interactions and special patient populations.