title: Morphine glucuronosyltransferase activity in human liver microsomes is inhibited by a variety of drugs that are co-administered with morphine.
abstract: Morphine is an analgesic drug used for the treatment of acute and chronic pain syndromes for cancer patients. Glucuronidation is a major pathway of the elimination of morphine in humans. Morphine is metabolized to 3-glucuronide (no analgesic effect) and 6-glucuronide (more potently analgesic than morphine) mainly by UGT2B7. In the present study, we investigated the inhibitory effects of a variety of drugs on the morphine glucuronosyltransferase activities in human liver microsomes. Twenty-one drugs including anticancer drugs, immunosuppressants, analgesics, anticonvulsants, antidepressants, antipsychotic drugs were selected in this study, because they are frequently co-administered with morphine. We found that 10 out of 21 drugs, tamoxifen, tacrolimus, diclofenac, carbamazepine, imipramine, clomipramine, amitriptyline, diazepam, lorazepam and oxazepam extensively inhibited the morphine 3- and 6-glucuronosyltransferase activities. Although some of the drugs are not substrates of UGT2B7, they would be potent inhibitors of UGT2B7. If patients receive morphine and these drugs simultaneously, the drug-drug interaction may change the levels of morphine and these glucuronides, resulting in altered analgesic efficacy and the risk of side effects. The results presented here will assist clinicians in choosing the proper drugs and/or dosages, and enable them to anticipate potential drug-drug interactions.
authors.affiliation: Drug Metabolism and Toxicology, Division of Pharmaceutical Sciences, Graduate School of Medical Science, Kanazawa University, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Hara
authors.forename: Miki
authors.initials: M
authors.lastname: Nakajima
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Miyamoto
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Yokoi
mesh_terms: D000701:Analgesics, Opioid / Q000378:metabolism*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008954:Models, Biological; D009020:Morphine / Q000378:metabolism*; D009022:Morphine Derivatives / Q000378:metabolism*; D011237:Predictive Value of Tests; D018570:Risk Assessment; D014535:Uridine Diphosphate Glucuronic Acid / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D004791:Enzyme Inhibitors; D020719:Glucuronides; D009022:Morphine Derivatives; D014535:Uridine Diphosphate Glucuronic Acid; C035349:morphine-6-glucuronide; D009020:Morphine; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase; C018108:morphine-3-glucuronide