Objective: The opioid alfentanil is a CYP3A4 substrate whose plasma clearance depends exclusively on hepatic CYP3A4 activity. Alfentanil clearance is an excellent in vivo probe for hepatic CYP3A4 activity and drug interactions in humans. However, such pharmacokinetic studies are invasive and time-consuming, and they require extensive analytical effort. This investigation tested the hypothesis that alfentanil-induced miosis (drug effect) can be used as a surrogate measure for alfentanil plasma concentrations and that alfentanil effect clearance will reflect plasma clearance; thus alfentanil can serve as a noninvasive probe for hepatic CYP3A4.
Methods: Six healthy volunteers were studied in a 3-way randomized crossover design. Each volunteer received 1 mg intravenous midazolam, followed 1 hour later by 15 microg/kg intravenous alfentanil, after CYP3A4 induction (rifampin [INN, rifampicin]), CYP3A4 inhibition (troleandomycin), and control. Dark-adapted pupil diameter and dynamic light response were measured coincident with venous blood sampling for up to 8 hours. Midazolam and alfentanil were quantified by gas chromatography-mass spectrometry. Plasma concentrations of alfentanil and midazolam (an additional CYP3A4 probe) and pupil diameter versus time data were analyzed by use of noncompartmental modeling. Pupil diameter change was analyzed analogously to determine the area under the alfentanil effect (miosis)-time curve (AUEC), effect clearance (CL(miosis)), and effect half-time.
Results: Compared with control, CYP3A4 induction and inhibition significantly altered the clearances of alfentanil (2.8 +/- 1.4, 5.3 +/- 1.0, and 0.42 +/- 0.1 ml/kg/min, respectively; P <.05 versus control) and midazolam. Dark-adapted resting diameter (in millimeters) was the best measure of alfentanil pupil effects. Alfentanil-dependent miosis was significantly altered by CYP3A4 modulation, and log(diameter(0) - diameter(t)) versus time curves resembled alfentanil plasma disposition. AUEC(infinity) values after control, CYP3A4 induction, and inhibition were 280 +/- 150, 120 +/- 22, and 1030 +/- 240 mm x min, respectively (P <.05 versus control). Effect clearances (CL(miosis)) were 4.2 +/- 1.3, 8.8 +/- 2.4, and 1.2 +/- 0.8 microg/mm x min, respectively, and effect half-times were 62 +/- 23, 34 +/- 27, and 211 +/- 35 minutes, respectively (P <.05 versus control). CL(miosis) was significantly correlated with plasma clearances of alfentanil (r = 0.77, P <.001) and midazolam (r = 0.80; P <.001).
Conclusions: Alfentanil effect (miosis) may be a sensitive and reliable surrogate for plasma alfentanil concentrations. Alfentanil effect kinetics may be used as a noninvasive surrogate for conventional pharmacokinetics. CL(miosis) appears to be a suitable noninvasive in vivo probe for hepatic CYP3A4 activity, and it merits further investigation.