No correlations between the urinary ratio of 6beta-hydroxycortisol to free cortisol and pharmacokinetics of alprazolam.
OBJECTIVE
The urinary ratio of 6beta-hydroxycortisol to cortisol is known as a possible marker of CYP3A4 activity. We investigated the correlation between this ratio and the disposition of alprazolam, which is a substrate of CYP3A4.


METHODS
Twelve healthy volunteers took a single dose (0.8 mg) of alprazolam at 0800 hours. Blood samplings were conducted up to 48 h after the dosing. Urine was collected during the 24 h prior to dosing. Quantification of alprazolam in plasma and that of cortisol and 6beta-hydroxycortisol in urine was performed using high-performance liquid chromatography.


RESULTS
Mean (+/-SD) values of peak plasma concentration (Cmax), time to Cmax (tmax), area under the plasma concentration-time curve [AUC(0-48)] and elimination half-life (tl/2) of alprazolam were 12.0+/-3.0 ng/ml, 1.5+/-0.9 h, 200+/-41 ng/ml h and 16.0+/-4.3 h, respectively. Mean (+/-SD) urinary ratio of 6beta-hydroxycortisol to cortisol was 3.28+/-0.67. No significant correlations were found between urinary ratio of 6beta-hydroxycortisol to cortisol and any pharmacokinetic parameters of alprazolam (Cmax: rs= -0.06; tmax: r(s)= 0.34; AUC(0-48): rs=0.08; t1/2: r(s)= -0.36).


CONCLUSIONS
This study suggests that the urinary ratio of 6beta-hydroxycortisol to cortisol is unlikely to predict pharmacokinetics of alprazolam.
Yasui-Furukori
N
N
Department of Clinical Pharmacology, Hirosaki University School of Medicine, Japan.
Kondo
T
T
Kubota
T
T
Otake
H
H
Ohkubo
T
T
Nagasaki
T
T
Sugawara
K
K
Chiba
K
K
Otani
K
K
Kaneko
S
S
D000328:Adult; D000525:Alprazolam / Q000097:blood / Q000493:pharmacokinetics*; D014151:Anti-Anxiety Agents / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D006854:Hydrocortisone / Q000031:analogs & derivatives* / Q000652:urine*; D008297:Male; D006899:Mixed Function Oxygenases / Q000378:metabolism
D014151:Anti-Anxiety Agents; C001380:6 beta-hydroxycortisol; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D006854:Hydrocortisone; D000525:Alprazolam