Morphine Glucuronosyltransferase Activity in Human Liver Microsomes is Inhibited by a Variety of Drugs that are Co-administered with Morphine

Abstract

Summary: 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 eŠect) and 6-glucuronide (more potently analgesic than morphine) mainly by UGT2B7. In the present study, we investigated the inhibitory eŠects of a variety of drugs on the morphine glucuronosyltransferase activities in human liver microsomes. Twenty-one drugs including anticancer drugs, immunosuppresants, analgesics, anticonvulsants, antidepressants, antipsychotic drugs were selected in this study, because they are frequently coadministered 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 e‹cacy and the risk of side eŠects. The results presented here will assist clinicians in choosing the proper drugs and W or dosages, and enable them to anticipate potential drug-drug interactions.

<i>In Vivo</i> Interaction of Morphine and Diclofenac

“…Morphine glucuronosyltransferase activity was determined as described by Hara et al [5]. A typical incubation mixture (0.2 mL total volume) contained 50 mM Tris-HCl buffer (pH 7.4), 5 mM MgCl 2 , 5 mM UDPGA, 25 µg/mL alamethicin, 0.25 mg/mL microsomal protein, and 25 -200 µM morphine.…”

“…Diclofenac has previously been demonstrated to induce a marked inhibition of morphine glucuronidation in human liver tissue homogenate [5] [6]. Because morphine clearance is dependent on UGTs, its inhibition by diclofenac may lead to decreased M3G formation, modifying the total effect of opioid.…”

Automation and Miniaturization of the Bioluminescent UGT-Glo Assay for Screening of UDP-Glucuronosyltransferase Inhibition by Various Compounds

“…23 Benazepril had little effect on UGT2B7 and UGT1A4, but inhibited UGT1A1 with an IC 50 of 69 mM (Fig. 3H, Table 2).…”

Morphine Metabolism in Human Skin Microsomes

“…In accordance with previous results [11], we investigated two morphine concentrations in the microsome assay. Microsomal glucuronidation assays are commonly used for biotransformation studies of chemicals and active pharmaceutical substances such as morphine, acetaminophen and testosterone [18,19]. In order to ensure that both types of microsomes are active, testosterone was incubated to prove the CYP activity (data not shown).…”