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.
Footnotes
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This study was supported by the National Health and Medical Research Council of Australia [Grant 480417]. V.U. was supported by an Australian Education International Endeavor Fellowship (Department of Education, Employment, and Workplace Relations, Australian Federal Government). P.R. was supported by a Prince of Songkla University Graduate Studies grant.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.167916.
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- COD
- codeine
- AUC
- area under the drug plasma concentration–time curve
- BSA
- bovine serum albumin
- C6G
- codeine-6-glucuronide
- CLH
- hepatic clearance
- DDI
- inhibitory drug–drug interaction
- HLM
- human liver microsomes
- IV-IVE
- in vitro–in vivo extrapolation
- Ki
- inhibitor constant
- Km
- Michaelis constant
- UGT
- UDP-glucuronosyltransferase
- Vmax
- maximal velocity
- fuinc
- fraction unbound in incubations
- CYP2D6
- cytochrome P450 2D6
- HPLC
- high-performance liquid chromatography
- UDPGA
- UDP-glucuronic acid
- HEK
- human embryonic kidney.
- Received March 3, 2010.
- Accepted May 17, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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