title: 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.affiliation: Divisions of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden. hadi.molanaei@karolinska.se
authors.forename: Hadi
authors.initials: H
authors.lastname: Molanaei
authors.forename: Peter
authors.initials: P
authors.lastname: Stenvinkel
authors.forename: Abdul Rashid
authors.initials: AR
authors.lastname: Qureshi
authors.forename: Juan Jesús
authors.initials: JJ
authors.lastname: Carrero
authors.forename: Olof
authors.initials: O
authors.lastname: Heimbürger
authors.forename: Bengt
authors.initials: B
authors.lastname: Lindholm
authors.forename: Ulf
authors.initials: U
authors.lastname: Diczfalusy
authors.forename: Ingegerd
authors.initials: I
authors.lastname: Odar-Cederlöf
authors.forename: Leif
authors.initials: L
authors.lastname: Bertilsson
mesh_terms: D000328:Adult; D000368:Aged; D000465:Algorithms; D000525:Alprazolam / Q000009:adverse effects / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D014151:Anti-Anxiety Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D015415:Biomarkers / Q000097:blood; D001711:Biotransformation; D002097:C-Reactive Protein / Q000032:analysis; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D005260:Female; D006801:Humans; D006888:Hydroxycholesterols / Q000097:blood; D006900:Hydroxylation; D008297:Male; D008875:Middle Aged; D009961:Orosomucoid / Q000032:analysis; D006435:Renal Dialysis; D051436:Renal Insufficiency, Chronic / Q000097:blood / Q000276:immunology / Q000378:metabolism*
chemical_list: D014151:Anti-Anxiety Agents; D015415:Biomarkers; D006888:Hydroxycholesterols; D009961:Orosomucoid; C032318:alpha-hydroxyalprazolam; D002097:C-Reactive Protein; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C503150:4-hydroxyalprazolam; D000525:Alprazolam