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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
Publication year - 2011
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.2010.313
Subject(s) - cyp3a , pharmacology , chemistry , pharmacokinetics , alfentanil , dosing , ketoconazole , oral administration , cytochrome p450 , medicine , metabolism , biochemistry , fentanyl , antifungal , dermatology
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. Clinical Pharmacology & Therapeutics (2011) 89 4, 562–570. doi: 10.1038/clpt.2010.313