Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/61833
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Type: Journal article
Title: In vitro-in vivo extrapolation predicts drug-drug interactions arising from inhibition of codeine glucuronidation by dextropropoxyphene, fluconazole, ketoconazole, and methadone in humans
Author: Raungrut, P.
Uchaipichat, V.
Elliot, D.
Janchawee, B.
Somogyi, A.
Miners, J.
Citation: Journal of Pharmacology and Experimental Therapeutics, 2010; 334(2):609-618
Publisher: Amer Soc Pharmacology Experimental Therapeutics
Issue Date: 2010
ISSN: 0022-3565
1521-0103
Statement of
Responsibility: 
Pritsana Raungrut, Verawan Uchaipichat, David J. Elliot, Benjamas Janchawee, Andrew A. Somogyi and John O. Miners
Abstract: Because codeine (COD) is eliminated primarily via glucuronidation, factors that alter COD glucuronide formation potentially affect the proportion of the dose converted to the pharmacologically active metabolite morphine. Thus, in vitro–in vivo extrapolation approaches were used to identify potential drug–drug interactions arising from inhibition of COD glucuronidation in humans. Initial studies characterized the kinetics of COD-6-glucuronide (C6G) formation by human liver microsomes (HLM) and demonstrated an 88% reduction in the Michaelis constant (Km) (0.29 versus 2.32 mM) for incubations performed in the presence of 2% bovine serum albumin (BSA). Of 13 recombinant UDP-glucuronosyltransferase (UGT) enzymes screened for COD glucuronidation activity, only UGT2B4 and UGT2B7 exhibited activity. The respective S50 values (0.32 and 0.27 mM) generated in the presence of BSA were comparable with the mean Km observed in HLM. Known inhibitors of UGT2B7 activity in vitro or in vivo and drugs marketed as compound formulations with COD were investigated for inhibition of C6G formation by HLM. Inhibition screening identified potential interactions with dextropropoxyphene, fluconazole, ketoconazole, and methadone. Inhibitor constant values generated for dextropropoxyphene (3.5 μM), fluconazole (202 μM), ketoconazole (0.66 μM), and methadone (0.32 μM) predicted 1.60- to 3.66-fold increases in the area under the drug plasma concentration–time curve ratio for COD in vivo. Whereas fluconazole and ketoconazole inhibited UGT2B4- and UGT2B7-catalyzed COD glucuronidation to a similar extent, inhibition by dextropropoxyphene and methadone resulted largely from an effect on UGT2B4. Interactions with dextropropoxyphene, fluconazole, ketoconazole, and methadone potentially affect the intensity and duration of COD analgesia.
Keywords: Microsomes, Liver; Animals; Cattle; Humans; Methadone; Codeine; Fluconazole; Ketoconazole; Glucuronosyltransferase; Serum Albumin, Bovine; Analgesics, Opioid; Drug Interactions; Models, Biological; Dextropropoxyphene
Rights: Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
RMID: 0020100459
DOI: 10.1124/jpet.110.167916
Appears in Collections:Pharmacology publications

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