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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

From the Departments of Anesthesiology and Medicinal Chemistry, University of Washington, Seattle. Supported by NIH grants R01-GM63674, R01-DA14211 and K24-DA00417 (EDK), and M01-RR00037 to the University of Washington General Clinical Research Center and by a grant from Pfizer, Inc.

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 by 3 mg 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.

Key Words: CYP3A • alfentanil • midazolam • miosis • drug metabolism

Address for reprints: Evan D. Kharasch, MD, PhD, Professor, Department of Anesthesiology, University of Washington, Box 356540, 1959 NE Pacific, RR-442, Seattle, WA 98195; e-mail: kharasch{at}u.washington.edu.

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