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Concurrent assessment of hepatic and intestinal cytochrome P450 3A activities using deuterated alfentanil.

Author(s): Kharasch ED, Vangveravong S, Buck N, London A, Kim T, Blood J, Mach RH

Affiliation(s): Division of Clinical and Translational Research, Department of Anesthesiology, Washington University in St. Louis, St. Louis, Missouri, USA. Kharasch@wustl.edu

Publication date & source: 2011-04, Clin Pharmacol Ther., 89(4):562-70. Epub 2011 Feb 23.

Publication type: Comparative Study; Randomized Controlled Trial; Research Support, N.I.H., Extramural

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.

Page last updated: 2011-12-09

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