Alfentanil-induced miosis clearance as a liver CYP3A4 and 3A5 activity measure in healthy volunteers: improvement of experimental conditions.
The aims of this study were to demonstrate the correlation between alfentanil-induced miosis evaluation and alfentanil pharmacokinetics (PK) as a CYP3A4 and 3A5 activity probe in volunteers and to explain the variability in pupilar response and in alfentanil PK. In ambient light, the miosis kinetic parameters were significantly correlated with PK (CLs: r = 0.9, P = .00; AUCs: r = 0.8, P = .01). In dark, a similar correlation was observed between miosis and alfentanil clearances (r = 0.85, P = .03). In 6 volunteers, the sigmoid E(max) model was applicable (average E(max) = 2.5 +/- 0.7 mm, gamma = 2.5 +/- 1.6 and EC(50) = 76.8 +/- 22.3 ng/mL), and in 3, the simple E(max) model was applicable (average E(max) = 2.8 +/- 0.3 mm and EC(50) = 19.9 +/- 8.5 ng/mL). There was a large interindividual variability in PK parameters (coefficient of variation = 19.7%-31.2%). Free drug fraction concentrations were negatively correlated with plasma alpha(1)-AGP (r = -0.9, P = .04) and albumin levels (r = -0.94, P = .02). Alfentanil-induced miosis clearance as a noninvasive CYP3A4 and 3A5 activity measure can be done in both ambient and dark conditions. Drug free fraction may be responsible for large intersubject variability in alfentanil PK.
Baririan
Narine
N
Department of Gastroenterology, Cliniques Universitaires Saint-Luc, Avenue Hippocrate, 10, Brussels 1200, Belgium.
Horsmans
Yves
Y
Desager
Jean-Pierre
JP
Verbeeck
Roger
R
Vanbinst
Roger
R
Wallemacq
Pierre
P
Van Obbergh
Luc
L
D000328:Adult; D015760:Alfentanil / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D015877:Miosis / Q000139:chemically induced*
D000701:Analgesics, Opioid; D015760:Alfentanil; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human