Metabolism of alprazolam (a marker of CYP3A4) in hemodialysis patients with persistent inflammation

Eur J Clin Pharmacol. 2012 May;68(5):571-7. doi: 10.1007/s00228-011-1163-8. Epub 2011 Dec 9.

Abstract

Objective: To investigate the impact of persistent inflammation in hemodialysis (HD) patients on the pharmacokinetics of alprazolam, a cytochrome P450 (CYP) 3A4 substrate, and its metabolites and the role of HD in the impact of persistent inflammation in this clinical context.

Methods: The study population comprised 26 HD patients (mean age 64 years, range 27-79 years; 19 men, 7 women) who were given 1 mg of alprazolam orally in the evening before the day of HD. Unconjugated and conjugated alprazolam and its 4-hydroxy and α-hydroxy metabolites were measured by liquid chromatography-mass spectrometry at 10, 34 (start of HD) and 38 (end of HD) h after intake. C-reactive protein (CRP) was measured weekly beginning 2 months before study initiation, and alpha 1-acid glycoprotein and 4β-hydroxycholesterol were measured at baseline. CYP3A4 activity was estimated as the ratio of unconjugated alprazolam to 4-hydroxyalprazolam between 10 and 34 h following alprazolam intake.

Results: After a single dose of alprazolam, plasma concentrations of unconjugated alprazolam and its metabolites decreased gradually, and unconjugated 4-hydroxyalprazolam was eliminated more rapidly than unconjugated alprazolam by HD. In contrast, the plasma concentrations of conjugated alprazolam and its conjugated metabolites increased during the 34 h following drug intake and the subsequent HD decreased their levels by almost 80%. The ratio of unconjugated alprazolam to 4-hydroxyalprazolam was correlated with CRP levels (r(s) = 0.49, P = 0.01). There was no significant correlation between CYP3A4 activity measured by alprazolam (4-hydroxylation) and alpha 1-acid glycoprotein or 4β-hydroxycholesterol. Conjugated alprazolam was also found in the plasma.

Conclusions: The correlation between CYP3A4 activity (assessed by alprazolam 4-hydroxylation) and CRP level suggests that inflammation may downregulate CYP3A4 activity. If confirmed, this could have major implications for drug dosing in persistently inflamed patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Algorithms
  • Alprazolam / adverse effects
  • Alprazolam / analogs & derivatives
  • Alprazolam / blood
  • Alprazolam / pharmacokinetics*
  • Anti-Anxiety Agents / adverse effects
  • Anti-Anxiety Agents / blood
  • Anti-Anxiety Agents / pharmacokinetics
  • Biomarkers / blood
  • Biotransformation
  • C-Reactive Protein / analysis
  • Cytochrome P-450 CYP3A / metabolism*
  • Female
  • Humans
  • Hydroxycholesterols / blood
  • Hydroxylation
  • Male
  • Middle Aged
  • Orosomucoid / analysis
  • Renal Dialysis*
  • Renal Insufficiency, Chronic / blood
  • Renal Insufficiency, Chronic / immunology
  • Renal Insufficiency, Chronic / metabolism*

Substances

  • Anti-Anxiety Agents
  • Biomarkers
  • Hydroxycholesterols
  • Orosomucoid
  • alpha-hydroxyalprazolam
  • C-Reactive Protein
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • 4-hydroxyalprazolam
  • Alprazolam