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Alfentanil‐Induced Miosis Clearance as a Liver CYP3A4 and 3A5 Activity Measure in Healthy Volunteers: Improvement of Experimental Conditions
Author(s) -
Baririan Narine,
Horsmans Yves,
Desager JeanPierre,
Verbeeck Roger,
Vanbinst Roger,
Wallemacq Pierre,
Obbergh Luc
Publication year - 2005
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270005282629
Subject(s) - alfentanil , miosis , pharmacokinetics , chemistry , anesthesia , cyp3a4 , pharmacology , medicine , biochemistry , metabolism , fentanyl , cytochrome p450
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 , γ = 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 α 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 .