Miosis following intravenous and oral alfentanil as a noninvasive probe for hepatic and first-pass CYP3A activity

Purpose Systemic clearance of IV alfentanil (ALF) is an in vivo probe for hepatic CYP3A, miosis is a surrogate for plasma ALF, & IV ALF miosis is a suitable noninvasive probe for hepatic CYP3A. This study determined whether oral ALF & miosis could probe first-pass CYP3A activity. Midazolam (MDZ) was also used to measure CYP3A. Methods Volunteers (10) were studied in a randomized 9-way crossover, after 5d rifampin (liver & gut CYP3A induction), troleandomycin (TAO, liver & gut CYP3A inhibition), grapefruit juice (GFJ, selective gut CYP3A inhibition), or nothing (control). They received MDZ 1mg IV then (1 hr later) ALF 15 ig/kg IV; at another visit 3 mg oral MDZ then (1 hr) oral ALF (23 or 60 ig/kg). Blood (MDZ & ALF by LCMS) & dark-adapted pupil diameters were measured & analyzed (noncompartmental). Results Bioavailability (F), hepatic extraction (EH) & GI availability (FGI) were 0.26, 0.55 & 0.60 for MDZ and 0.42, 0.29 & 0.62 for ALF. After rifampin, TAO & GFJ, ALF F was 0.02, 1 & 0.67; EH was 0.71, 0.04 & 0.26. FGI was 0.07, 1 & 0.92. There were excellent correlations between IV ALF & MDZ systemic clearance (r2=0.92), oral ALF & MDZ CL/F (r2=0.97), and dose-adjusted AUCs for miosis & plasma ALF. Conclusions Systemic & oral CL of IV & oral ALF are excellent in vivo probes for hepatic & first-pass CYP3A activity & interactions. Miosis was an acceptable surrogate for plasma ALF. ALF miosis may be a suitable noninvasive in vivo probe for hepatic & first-pass CYP3A. Clinical Pharmacology & Therapeutics (2004) 75, P81–P81; doi: 10.1016/j.clpt.2003.11.309