title: Effects of ketamine on human UDP-glucuronosyltransferases in vitro predict potential drug-drug interactions arising from ketamine inhibition of codeine and morphine glucuronidation.
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, IC(50) 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. K(i) 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.
authors.affiliation: Department of Clinical Pharmacology, Flinders University School of Medicine, Adelaide, Australia.
authors.forename: Verawan
authors.initials: V
authors.lastname: Uchaipichat
authors.forename: Pritsana
authors.initials: P
authors.lastname: Raungrut
authors.forename: Nuy
authors.initials: N
authors.lastname: Chau
authors.forename: Benjamas
authors.initials: B
authors.lastname: Janchawee
authors.forename: Allan M
authors.initials: AM
authors.lastname: Evans
authors.forename: John O
authors.initials: JO
authors.lastname: Miners
mesh_terms: D000701:Analgesics, Opioid / Q000378:metabolism / Q000493:pharmacokinetics*; D000818:Animals; D018929:Cell Culture Techniques; D003061:Codeine / Q000378:metabolism / Q000493:pharmacokinetics*; D003470:Culture Media; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors* / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D008658:Inactivation, Metabolic; D007313:Insecta; D007649:Ketamine / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D009020:Morphine / Q000378:metabolism / Q000493:pharmacokinetics*; D011237:Predictive Value of Tests; D011485:Protein Binding; D014162:Transfection
chemical_list: D000701:Analgesics, Opioid; D003470:Culture Media; D007649:Ketamine; D009020:Morphine; D014453:Glucuronosyltransferase; D003061:Codeine