Disposition and miotic effects of oral alfentanil: A potential noninvasive probe for first-pass cytochrome P4503A activity

Background and objectives: Systemic clearance of the opioid alfentanil after intravenous administration is an excellent in vivo probe for hepatic cytochrome P4503A (CYP3A) activity and drug interactions. Alfentanil effect (miosis) is a surrogate for plasma alfentanil concentrations, and alfentanil effect kinetics may be a suitable noninvasive probe for hepatic CYP3A. Oral alfentanil might be a probe for first-pass CYP3A activity; however, it is not used clinically, and oral alfentanil disposition is unknown. This investigation evaluated the disposition and miotic effects of oral alfentanil. Methods: Ten healthy volunteers were studied in a dose-escalation fashion, receiving 23, 30, 43, and 75 mug/kg oral alfentanil on different days. Dark-adapted pupil diameter was measured at the time of venous blood sampling. Alfentanil was quantified by liquid chromatography-mass spectrometry. Plasma concentrations of alfentanil and pupil diameter change versus time data were analyzed by noncompartmental modeling. Results: Alfentanil was rapidly absorbed (time to maximum concentration [T-max], 0.7 +/- 0.5 hour). Mean values for area under the plasma concentration-time curve extrapolated to infinity (AUC(infinity)) (27 +/- 14, 38 +/- 22, 57 +/- 31, and 105 +/- 59 ng . h . mL(-1)) and maximum concentration (16 +/- 8, 23 +/- 16, 31 +/- 18, and 50 +/- 22 ng/mL) were linear with dose, although there was considerable interindividual variability. T-max, elimination half-life (1.0 +/- 0.2 hours), total body clearance after oral administration (20 +/- 18 mL . kg(-1) . min(-1)), and dose-normalized AUC(infinity) were independent of dose. Dose-dependent alfentanil disposition was mirrored by commensurate changes in clinical effect, although miosis was variable and not detectable in all subjects at the lowest dose. Mean miosis AUC (AUEC) and peak miosis were log-dose linear. Effect half-life (1.3 +/- 0.9 hours) was similar to plasma half-life. Conclusion: Oral alfentanil is rapidly absorbed, exhibits linear and dose-independent kinetics, and undergoes substantial first-pass metabolism. Oral alfentanil may be a suitable probe for first-pass CYP3A activity. Alfentanil effect (miosis) may be an acceptable surrogate for plasma alfentanil concentrations. Oral alfentanil effect may be a noninvasive surrogate for conventional pharmacokinetics. Further studies are warranted to determine whether oral alfentanil and alfentanil effect kinetics may be a suitable noninvasive in vivo probe for first-pass CYP3A activity. (Clin Pharmacol Ther 2003;73:199-208.).