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Sensitivity of Intravenous and Oral Alfentanil and Pupillary Miosis as Minimally Invasive and Noninvasive Probes for Hepatic and First‐Pass CYP3A Activity
Author(s) -
Kharasch Evan D.,
Walker Alysa,
Hoffer Christine,
Sheffels Pamela
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 - 10.1177/0091270005280077
Subject(s) - alfentanil , midazolam , fluconazole , medicine , anesthesia , cyp3a , pharmacokinetics , crossover study , pharmacology , sedation , placebo , fentanyl , antifungal , cytochrome p450 , dermatology , metabolism , alternative medicine , pathology
This investigation determined the ability of alfentanil miosis and single‐point concentrations to detect various degrees of CYP3A inhibition. Results were compared with those for midazolam, an alternative CYP3A probe. Twelve volunteers were studied in a randomized 4‐way crossover, targeting 12%, 25%, and 50% inhibition of hepatic CYP3A. They received 0, 100, 200, or 400 mg oral fluconazole, followed 1 hour later by 1 mg intravenous midazolam and then 15 μg/kg intravenous alfentanil 1 hour later. The next day, they received fluconazole, followed by3mg oral midazolam and 40 μg/kg oral alfentanil. Dark‐adapted pupil diameters were measured coincident with blood sampling. Area under the plasma concentration‐time curve (AUC) ratios (fluconazole/control) after 100,200, and 400 mg fluconazole were (geometric mean) 1.3*, 1.4*, and 2.0* for intravenous midazolam and 1.2*, 1.6*, and 2.2* for intravenous alfentanil (* significantly different from control), indicating 16% to 21%, 31% to 36%, and 43% to 53% inhibition of hepatic CYP3A. Single‐point concentration ratios were 1.5*, 1.8*, and 2.4* for intravenous midazolam (at 5 hours) and 1.2*, 1.6*, and 2.2* for intravenous alfentanil (at 4 hours). Pupil miosis AUC ratios were 0.9, 1.0, and 1.2*. After oral dosing, plasma AUC ratios were 2.3*, 3.6*, and 5.3* for midazolam and 1.8*, 2.9*, and 4.9* for alfentanil; plasma single‐point ratios were 2.4*, 4.5*, and 6.9* for midazolam and 1.8*, 2.9*, and 4.9* for alfentanil, and alfentanil miosis ratios were 1.1, 1.9*, and 2.7*. Plasma concentration AUC ratios of alfentanil and midazolam were equivalent for detecting hepatic and first‐pass CYP3A inhibition. Single‐point concentrations were an acceptable surrogate for formal AUC determinations and as sensitive as AUCs for detecting CYP3A inhibition. Alfentanil miosis could detect 50% to 70% inhibition of CYP3A activity, but was less sensitive than plasma AUCs. Further refinements are needed to increase the sensitivity of alfentanil miosis for detecting small CYP3A changes.