O-demethylation of codeine to morphine inhibited by low-dose levomepromazine

Vevelstad, Merete; Pettersen, S; Tallaksen, Chantal; Brørs, Odd

doi:10.1007/s00228-009-0640-9

Cited by 19 publications

(8 citation statements)

References 17 publications

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“…These results are in contrast with other human studies which demonstrated analgesic efficacy of levomepromazine [25,26]. It should also be noted that levomepromazine in rats [27] and in humans [28] and metoclopramide in humans [29] significantly inhibit CYP2D6 activity. Further research is needed to fully elucidate the results obtained in our study.…”

Section: Discussioncontrasting

confidence: 55%

Analgesic Effects of Morphine in Combination with Adjuvant Drugs in Rats

Leppert¹,

Okulicz-Kozaryn

Kamińska

et al. 2014

Pharmacology

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Background: Morphine is co-administered with adjuvant drugs to treat pain, nausea, vomiting, dyspnoea and delirium in cancer patients. Aim of the Study: To investigate analgesic effects of morphine when co-administered with adjuvant drugs. Material and Methods: Two-month-old male Wistar rats received single morphine doses alone (0.45 and 0.9 mg/kg) or with midazolam (0.3 mg/kg), haloperidol (0.15 and 0.45 mg/kg), levomepromazine (0.35 mg/kg), metoclopramide (1.0 mg/kg), and hyoscine butylbromide (1.7 mg/kg) as single subcutaneous injections. Analgesia was measured by the tail-flick test after 15, 30, 45, 60, and 90 min of drug administration. In the case of significant analgesia enhancement, analgesic and sedative effects were explored in 3-, 5-, 6-, 8-, and 11-month-old rats. Results: Significant morphine (0.9 mg/kg) analgesia enhancement was observed 60 min after haloperidol (0.15 and 0.45 mg/kg) and hyoscine butylbromide co-administration. The addition of haloperidol to morphine significantly increased analgesia in 6-, 8- and 11-month-old rats while in the case of hyoscine butylbromide co-administration this effect was observed only in 11-month-old rats. Conclusions: Haloperidol and hyoscine butylbromide enhanced morphine analgesia. Future studies may explore the repeated administration of these drug combinations in rats and humans. i 2014 S. Karger AG, Basel

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Section: Discussioncontrasting

confidence: 55%

Analgesic Effects of Morphine in Combination with Adjuvant Drugs in Rats

Leppert¹,

Okulicz-Kozaryn

Kamińska

et al. 2014

Pharmacology

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“…Clinical DDIs between CYP2D6 substrate and inhibitors have been reported previously. A significant inhibition in the O-demethylation of codeine to morphine in homozygous extensive metabolizer of CYP2D6 treated with low-dose levomepromazine has been documented (Vevelstad et al, 2009). A reported clinical DDI between flecainide and paroxetine has led to the suggestion of monitoring plasma flecainide concentrations for those who are on CYP2D6 inhibitors, such as paroxetine, quinidine, and possibly GFA (Tsao and Gugger, 2009).…”

Section: Discussionmentioning

confidence: 99%

Guanfu Base A, an Antiarrhythmic Alkaloid ofAconitum coreanum, Is a CYP2D6 Inhibitor of Human, Monkey, and Dog Isoforms

Sun

Peng

et al. 2015

Drug Metab Dispos

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Guanfu base A (GFA) is a novel heterocyclic antiarrhythmic drug isolated from Aconitum coreanum (Lèvl.) rapaics and is currently in a phase IV clinical trial in China. However, no study has investigated the influence of GFA on cytochrome P450 (P450) drug metabolism. We characterized the potency and specificity of GFA CYP2D inhibition based on dextromethorphan O-demethylation, a CYP2D6 probe substrate of activity in human, mouse, rat, dog, and monkey liver microsomes. In addition, (+)-bufuralol 19-hydroxylation was used as a CYP2D6 probe for the recombinant form (rCYP2D6), 2D1 (rCYP2D1), and 2D2 (rCYP2D2) activities. Results show that GFA is a potent noncompetitive inhibitor of CYP2D6, with inhibition constant K i = 1.20 6 0.33 mM in human liver microsomes (HLMs) and K i = 0.37 6 0.16 mM for the human recombinant form (rCYP2D6). GFA is also a potent competitive inhibitor of CYP2D in monkey (K i = 0.38 6 0.12 mM) and dog (K i = 2.4 6 1.3 mM) microsomes. However, GFA has no inhibitory activity on mouse or rat CYP2Ds. GFA did not exhibit any inhibition activity on human recombinant CYP1A2, 2A6, 2C8, 2C19, 3A4, or 3A5, but showed slight inhibition of 2B6 and 2E1. Preincubation of HLMs and rCYP2D6 resulted in the inactivation of the enzyme, which was attenuated by GFA or quinidine. Beagle dogs treated intravenously with dextromethorphan (2 mg/ml) after pretreatment with GFA injection showed reduced CYP2D metabolic activity, with the C max of dextrorphan being one-third that of the saline-treated group and area under the plasma concentration-time curve half that of the saline-treated group. This study suggests that GFA is a specific CYP2D6 inhibitor that might play a role in CYP2D6 medicated drug-drug interaction.

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“…Analgesic efficacy of LEV was also seen in studies conducted in humans [27,39]. It should also be noted that LEV in rats [40] and humans [41] and MET in humans [42] significantly inhibit CYP2D6 activity, which may increase Apart from the analgesic effects, some of the explored compounds such as neuroleptics (HAL and LEV) and benzodiazepine (MID) might have also induced additional sedative and anesthetic effects, in addition to analgesic ones, as part of their pharmacodynamics. In the test exploring the anti-inflammatory effect, carrageenan was used for inducing inflammation, and each rat received 2000 µg of carrageenan as a 0.2 mL solution at a concentration of 1%.…”

Section: Research Wojciech Leppertmentioning

confidence: 94%

Analgesic and Anti–Inflammatory Effects of Oxycodone with Adjuvant Drugs in an Experimental Study of Nociceptive and Neuropathic Pain

Leppert¹,

Szulc²,

Kaczmarek³

et al. 2018

Neuropsychiatry

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Objective: Opioids are often combined with adjuvants to treat symptoms that accompany pain and with adjuvant analgesics to treat neuropathic pain. Herein, we aim to investigate the analgesic and anti-inflammatory effects of oxycodone and selected adjuvants in rats.Methods: Analgesic and anti-inflammatory effects of oxycodone were assessed after single subcutaneous (SC) (0.56 mg/kg) injections in rats, with the following drugs: midazolam (0.3 mg/kg), haloperidol (0.45 mg/kg), ketamine (0.3 mg/kg), hyoscine butylbromide (1.7 mg/kg), levomepromazine (0.35 mg/kg), and metoclopramide (1.0 mg/kg). Analgesia was assessed by the tail flick test. Anti-inflammatory activity was evaluated using a plethysmometer after carrageenan-induced edema. For neuropathic pain, analgesia was explored using the tail flick and von Frey tests. Neuropathic pain was induced by vincristine (0.1 mg/kg, i.p.) in male Wistar rats.Results: All tested combinations of oxycodone with particular adjuvants showed increased analgesia in comparison to oxycodone alone. Compared to oxycodone alone, combinations with midazolam, haloperidol, hyoscine butylbromide, and levomepromazine prolonged analgesia. Anti-inflammatory activities were observed after coadministration of oxycodone paired with haloperidol and ketamine, which is a new aspect of the pharmacological profile of oxycodone. In the neuropathic pain model, vincristine lowered pain threshold in rats and inhibited growth of normal rat body weight. Oxycodone in combination with adjuvant analgesics showed more potent analgesia than oxycodone alone, especially in the tail-flick test. In most cases, the maximum effects were observed for 15-30 min since combined SC administration.Conclusions: Analgesic and anti-inflammatory effects were observed in oxycodone combined with selected adjuvants in rats; although the mechanism of these interactions is not yet well understood. Further studies should test these combinations after chronic administration and assess the benefits and risks associated with the use of the tested combinations in humans.

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O-demethylation of codeine to morphine inhibited by low-dose levomepromazine

Cited by 19 publications

References 17 publications

Analgesic Effects of Morphine in Combination with Adjuvant Drugs in Rats

Analgesic Effects of Morphine in Combination with Adjuvant Drugs in Rats

Guanfu Base A, an Antiarrhythmic Alkaloid ofAconitum coreanum, Is a CYP2D6 Inhibitor of Human, Monkey, and Dog Isoforms

Analgesic and Anti–Inflammatory Effects of Oxycodone with Adjuvant Drugs in an Experimental Study of Nociceptive and Neuropathic Pain

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