PT  - JOURNAL ARTICLE
AU  - Uchaipichat, Verawan
AU  - Raungrut, Pritsana
AU  - Chau, Nuy
AU  - Janchawee, Benjamas
AU  - Evans, Allan M
AU  - Miners, John O
TI  - Effects of ketamine on human UDP-glucuronosyltransferases in vitro predict potential drug-drug interactions arising from ketamine inhibition of codeine and morphine glucuronidation
AID  - 10.1124/dmd.111.039727
DP  - 2011 Jan 01
TA  - Drug Metabolism and Disposition
PG  - dmd.111.039727
4099  - http://dmd.aspetjournals.org/content/early/2011/05/06/dmd.111.039727.short
4100  - http://dmd.aspetjournals.org/content/early/2011/05/06/dmd.111.039727.full
AB  - The selectivity of UGT enzyme inhibition by ketamine KTM and the kinetics of KTM inhibition of human liver microsomal morphine (MOR) and codeine (COD) glucuronidation were characterized here to explore further 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-dependant 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% BSA were 5.8 ± 0.1 μM, 4.6 ± 0.2 μM, and 3.5 ± 0.1 μM, respectively. Based on the derived inhibitor constants, in vitro – in vivo extrapolation was employed 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 AUC ratios) with MOR and COD were predicted for anesthetic doses of KTM, and for a sub-anesthetic dose of KTM on COD glucuronidation.