Abstract
In this study, the selectivity of UDP-glucuronosyltransferase (UGT) enzyme inhibition by ketamine (KTM) and the kinetics of KTM inhibition of human liver microsomal morphine (MOR) and codeine (COD) glucuronidation were characterized to explore a pharmacokinetic basis for the KTM-opioid interaction. With the exception of UGT1A4, KTM inhibited the activities of recombinant human UGT enzymes in a concentration-dependent manner. However, IC50 values were <100 μM only for UGT2B4, UGT2B7, and UGT2B15. UGT2B7 catalyzes MOR 3- and 6-glucuronidation and the 6-glucuronidation of COD, with an additional substantial contribution of UGT2B4 to the latter reaction. Consistent with the effects of KTM on the activities of recombinant UGT2B enzyme activities, KTM competitively inhibited human liver microsomal MOR and COD glucuronidation. Ki values for KTM inhibition of MOR 3- and 6-glucuronidation and COD 6-glucuronidation by human liver microsomes supplemented with 2% bovine serum albumin were 5.8 ± 0.1, 4.6 ± 0.2, and 3.5 ± 0.1 μM, respectively. Based on the derived inhibitor constants, in vitro-in vivo extrapolation was used to predict the effects of anesthetic and analgesic doses of KTM on MOR and COD clearances. Potentially clinically significant interactions (>50% increases in the in vivo area under the curve ratios) with MOR and COD were predicted for anesthetic doses of KTM and for a subanesthetic dose of KTM on COD glucuronidation.
Footnotes
This study was supported by a grant from the National Health and Medical Research Council of Australia. V.U. was the recipient of an Australian Education International Endeavour Fellowship, and P.R. was supported in part by a Prince of Songkla University Graduate Studies grant.
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.111.039727.
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ABBREVIATIONS:
- KTM
- ketamine
- MOR
- morphine
- COD
- codeine
- C6G
- codeine-6-β-d-glucuronide
- UGT
- UDP-glucuronosyltransferase
- HLM
- human liver microsomes
- BSA
- bovine serum albumin
- IV-IVE
- in vitro-in vivo extrapolation
- 4MU
- 4-methylumbelliferone
- M3G
- morphine 3-β-d-glucuronide
- M6G
- morphine 6-β-d-glucuronide
- LTG
- lamotrigine
- HEK
- human embryonic kidney
- HPLC
- high-performance liquid chromatography
- fuinc
- unbound fraction of KTM in incubations
- AUC
- area under the plasma concentration-time curve.
- Received March 24, 2011.
- Accepted May 6, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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