title: Concurrent assessment of hepatic and intestinal cytochrome P450 3A activities using deuterated alfentanil.
abstract: Alfentanil (ALF) is a validated probe for hepatic, first-pass, and intestinal cytochrome P450 (CYP) 3A activity, using plasma clearances, single-point concentrations, and noninvasive pupil diameter change (miosis). Assessing intravenous (i.v.) and oral drug disposition typically requires separate dosing. This investigation evaluated concurrent administration of oral deuterated and i.v. unlabeled ALF to assess both intestinal and hepatic CYP3A, and compare sequential and simultaneous dosing. ALF disposition was evaluated after strong hepatic and/or intestinal CYP3A induction and inhibition by rifampin, ketoconazole, and grapefruit juice. Using plasma ALF concentrations and area under the curve (AUC), clearance, or single-point concentrations, both simultaneous and sequential dosing provided equivalent results and detected hepatic and intestinal CYP3A induction and inhibition. Miosis better detected CYP3A modulation with sequential vs. simultaneous dosing. These results show that concurrent administration of oral deuterated and i.v. ALF, either sequentially or simultaneously, is an efficient and effective approach to assessing hepatic and intestinal CYP3A activity.
authors.affiliation: Division of Clinical and Translational Research, Department of Anesthesiology, Washington University in St. Louis, St. Louis, Missouri, USA. Kharasch@wustl.edu
authors.forename: E D
authors.initials: ED
authors.lastname: Kharasch
authors.forename: S
authors.initials: S
authors.lastname: Vangveravong
authors.forename: N
authors.initials: N
authors.lastname: Buck
authors.forename: A
authors.initials: A
authors.lastname: London
authors.forename: T
authors.initials: T
authors.lastname: Kim
authors.forename: J
authors.initials: J
authors.lastname: Blood
authors.forename: R H
authors.initials: RH
authors.lastname: Mach
mesh_terms: D000284:Administration, Oral; D000328:Adult; D015760:Alfentanil / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D018686:Anesthetics, Intravenous / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D001628:Beverages; D032083:Citrus paradisi / Q000737:chemistry; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects / Q000378:metabolism*; D003903:Deuterium; D004334:Drug Administration Schedule; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007654:Ketoconazole / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D008297:Male; D015877:Miosis / Q000139:chemically induced*; D012293:Rifampin / Q000494:pharmacology; D055815:Young Adult
chemical_list: D018686:Anesthetics, Intravenous; D004791:Enzyme Inhibitors; D015760:Alfentanil; D003903:Deuterium; D051544:Cytochrome P-450 CYP3A; D007654:Ketoconazole; D012293:Rifampin