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

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.

• Authors: Hadi Molanaei, Peter Stenvinkel, Abdul Rashid Qureshi, Juan Jesús Carrero, Olof Heimbürger, Bengt Lindholm, Ulf Diczfalusy, Ingegerd Odar-Cederlöf, Leif Bertilsson
• Journal: European journal of clinical pharmacology (Eur J Clin Pharmacol) Vol. 68 Issue 5 Pg. 571-7 (May 2012) ISSN: 1432-1041 [Electronic] Germany
• PMID: 22159869 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• Adult
• Aged
• Algorithms
• Alprazolam (adverse effects, analogs & derivatives, blood, pharmacokinetics)
• Anti-Anxiety Agents (adverse effects, blood, 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, immunology, metabolism)