title: Sensitivity of intravenous and oral alfentanil and pupillary miosis as minimal and noninvasive probes for hepatic and first-pass CYP3A induction.
abstract: Systemic and oral clearances of alfentanil (ALF) are in vivo probes for hepatic and first-pass cytochrome P450 (CYP) 3A. Both ALF single-point plasma concentrations and miosis are surrogates for area under the concentration-time curve (AUC) and clearance and are minimal and noninvasive CYP3A probes. This investigation determined ALF sensitivity for detecting graded CYP3A induction and compared it with that of midazolam (MDZ). Twelve volunteers (sequential crossover) received 0, 5, 10, 25, or 75 mg oral rifampin for 5 days. MDZ and ALF were given intravenously and orally on sequential days. Dark-adapted pupil diameter was measured with blood sampling. Graded rifampin decreased plasma MDZ AUCs to 83, 76, 62, and 59% (intravenous (i.v.)) and 78, 66, 39, and 24% (oral) of control. Hepatic and first-pass CYP3A induction were detected comparably by plasma MDZ and ALF AUCs. Single ALF concentrations detected all CYP3A induction, whereas MDZ was less sensitive. ALF miosis detected induction of first-pass but not hepatic CYP3A.
authors.affiliation: Division of Clinical and Translational Research, Department of Anesthesiology, Washington University in St Louis, St Louis, Missouri, USA.
authors.forename: E D
authors.initials: ED
authors.lastname: Kharasch
authors.forename: A
authors.initials: A
authors.lastname: Francis
authors.forename: A
authors.initials: A
authors.lastname: London
authors.forename: K
authors.initials: K
authors.lastname: Frey
authors.forename: T
authors.initials: T
authors.lastname: Kim
authors.forename: J
authors.initials: J
authors.lastname: Blood
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D015760:Alfentanil / Q000008:administration & dosage / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D019540:Area Under Curve; D001682:Biological Availability; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis*; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006207:Half-Life; D006801:Humans; D006993:Hypnotics and Sedatives / Q000097:blood / Q000494:pharmacology; D007275:Injections, Intravenous; D007700:Kinetics; D007917:Leprostatic Agents / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology*; D008297:Male; D008874:Midazolam / Q000097:blood / Q000494:pharmacology; D015877:Miosis / Q000139:chemically induced*; D012293:Rifampin / Q000494:pharmacology; D012907:Smoking / Q000378:metabolism; D055815:Young Adult
chemical_list: D000701:Analgesics, Opioid; D006993:Hypnotics and Sedatives; D007917:Leprostatic Agents; D015760:Alfentanil; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam; D012293:Rifampin