title: In vitro-in vivo extrapolation predicts drug-drug interactions arising from inhibition of codeine glucuronidation by dextropropoxyphene, fluconazole, ketoconazole, and methadone in humans.
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 (K(m)) (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 S(50) values (0.32 and 0.27 mM) generated in the presence of BSA were comparable with the mean K(m) 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 microM), fluconazole (202 microM), ketoconazole (0.66 microM), and methadone (0.32 microM) 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.
authors.affiliation: Department of Clinical Pharmacology, Flinders University School of Medicine, Adelaide, Australia.
authors.forename: Pritsana
authors.initials: P
authors.lastname: Raungrut
authors.forename: Verawan
authors.initials: V
authors.lastname: Uchaipichat
authors.forename: David J
authors.initials: DJ
authors.lastname: Elliot
authors.forename: Benjamas
authors.initials: B
authors.lastname: Janchawee
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Somogyi
authors.forename: John O
authors.initials: JO
authors.lastname: Miners
mesh_terms: D000701:Analgesics, Opioid / Q000378:metabolism*; D000818:Animals; D002417:Cattle; D003061:Codeine / Q000031:analogs & derivatives* / Q000378:metabolism; D011431:Dextropropoxyphene / Q000494:pharmacology; D004347:Drug Interactions; D015725:Fluconazole / Q000494:pharmacology; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007654:Ketoconazole / Q000494:pharmacology; D008691:Methadone / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D012710:Serum Albumin, Bovine / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D012710:Serum Albumin, Bovine; D015725:Fluconazole; C061773:codeine-6-glucuronide; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase; C486404:UGT2B4 protein, human; D007654:Ketoconazole; D011431:Dextropropoxyphene; D008691:Methadone; D003061:Codeine