Persistently High Plasma Morphine-6-Glucuronide Levels Despite Decreased Hourly Patient-Controlled Analgesia Morphine Use After Single-Dose Diclofenac

Tighe, K. E.; Webb, Andrew M.; Hobbs, Gregory J.

doi:10.1213/00000539-199905000-00032

Cited by 28 publications

(25 citation statements)

References 18 publications

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“…In the presents study, we investigated the inhibitory effects of 21 drugs on the morphine glucuronosyltransferase activities. Although the Km values of the morphine glucuronosyltransferase activities are high as mM order, the inhibitory effects were investigated with the substrate concentrations at mM order by considering the plasma concentrations in clinical practice 11) and the detection limits of morphine glucuronides in the HPLC system.…”

Section: )mentioning

confidence: 99%

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

Hara

Nakajima

Miyamoto

et al. 2007

Drug Metabolism and Pharmacokinetics

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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.

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Section: )mentioning

confidence: 99%

“…Tighe et al 11) have reported that the plasma concentration of morphine 6-glucuronide was decreased by 40z with co-administration of diclofenac. Diclofenac is known to be mainly metabolized by P450s, but also metabolized by UGTs ( Table 2).…”

Section: )mentioning

confidence: 99%

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

Hara

Nakajima

Miyamoto

et al. 2007

Drug Metabolism and Pharmacokinetics

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“…These additive effects between Mor and NSAIDs were caused by different pharmacodynamic mechanisms; opioids display their analgesic activity in the central nervous system via opioids receptors, and NSAIDs reduce the synthesis of inflammatory prostaglandins via inhibition of the enzyme cyclooxygenase [1][2][3].…”

Section: Pharmacokinetic Interaction Between Mor and Dicmentioning

confidence: 99%

“…Furthermore, inhibition of renal clearance of Dic was expected as a pharmacokinetic mechanism of additive effect between Mor and Dic [3]. On the other hand, some reports were concluded that Dic did not interact pharmacokinetic of Mor in human [6].…”

Section: Pharmacokinetic Interaction Between Mor and Dicmentioning

confidence: 99%

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Sensitive HPLC–fluorescence detection of morphine labeled with DIB-Cl in rat brain and blood microdialysates and its application to the preliminarily study of the pharmacokinetic interaction between morphine and diclofenac

et al. 2008

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Effect of non‐prohibited drugs on the phase II metabolic profile of morphine. An in vitro investigation for doping control purposes

Ambrosio

Torre

Mazzarino

et al. 2018

Drug Testing and Analysis

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The potential consequences of drug-drug interaction on the strategies adopted by anti-doping laboratories to report an adverse analytical finding for morphine were investigated. We evaluated in vitro the effects of 14 drugs on the principal metabolic pathways of morphine. The selected drugs are among those most commonly used by the athletes, none of them presently included in the World Anti-Doping Agency (WADA) Prohibited List. The non-prohibited drugs included 4 antifungals (fluconazole, itraconazole, ketoconazole, and miconazole), 6 benzodiazepines (alprazolam, bromazepam, clonazepam, lorazepam, lormetazepam, and triazolam), and 4 non-steroidal anti-inflammatory drugs (diclofenac, ibuprofen, ketoprofen, and nimesulide). The in vitro assays were based on the use of either human liver microsomes or uridine 5'-diphospho-glucuronosyl-transferases. Morphine and its glucuronides were determined by developed liquid chromatography-mass spectrometry procedure after dilution with an aqueous solution containing their deuterated isotopologues as internal standards. Morphine is mainly excreted as phase II metabolites: about 70% of the parent compound is found to be biotransformed by UGT2B7 to morphine-3-glucuronide (6065%) and morphine-6-glucuronide (5-10%). A reduction of the enzymatic activity of the UGT2B7 was recorded in the presence of 9 of the 14 drugs under investigation (ketoconazole, miconazole, itraconazole, diclofenac, ibuprofen, clonazepam, lorazepam, lormetazepam, and triazolam), with a consequent significant reduction of the levels of the glucuronide metabolites. This phenomenon in vivo may affect the rate of the urinary excretion of morphine with the risk of reporting "false negative" results, especially in case of results close to the decision limit value set by WADA.

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Persistently High Plasma Morphine-6-Glucuronide Levels Despite Decreased Hourly Patient-Controlled Analgesia Morphine Use After Single-Dose Diclofenac

Cited by 28 publications

References 18 publications

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

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

Sensitive HPLC–fluorescence detection of morphine labeled with DIB-Cl in rat brain and blood microdialysates and its application to the preliminarily study of the pharmacokinetic interaction between morphine and diclofenac

Effect of non‐prohibited drugs on the phase II metabolic profile of morphine. An in vitro investigation for doping control purposes

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