Pivaloylcodeine, a new codeine derivative, for the inhibition of morphine glucuronidation. An in vitro study in the rat
| Autor: | Laura Guarcini, Rosario Nicoletti, Paolo Nencini, Letizia Antonilli, Giuseppina I. Togna, Filomena Sanasi, Armandodoriano Bianco, Giovanna Sabatini, Anna Rita Togna, Alessandro Venditti |
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| Rok vydání: | 2013 |
| Předmět: |
Male
Clinical Biochemistry Glucuronidation Pharmaceutical Science codeine glucuronidation liver microsomes pivaloylcodeine acetylcodeine morphine-3-glucuronide Pharmacology Biochemistry Rats Sprague-Dawley Structure-Activity Relationship chemistry.chemical_compound Drug Discovery medicine Animals Molecular Biology Morphine-3-glucuronide Morphine Derivatives Dose-Response Relationship Drug Molecular Structure Codeine Chemistry Organic Chemistry Dihydrocodeine Rats Kinetics Mechanism of action Hepatocytes Microsomes Liver Morphine Microsome Molecular Medicine Acetyldihydrocodeine medicine.symptom medicine.drug |
| Zdroj: | Bioorganic & Medicinal Chemistry. 21:7955-7963 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2013.09.062 |
| Popis: | We have previously found that phenanthrenic opioids, including codeine, modulate morphine glucuronidation in the rat. Here codeine and five of its derivatives were compared in their effects on the synthesis of morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) from morphine by rat liver microsomal preparations, and by primary cultures of rat hepatocytes previously incubated for 72 h with either codeine or its derivatives. Acetylcodeine and pivaloylcodeine shared the capability of the parent compound of inhibiting the synthesis of M3G by liver microsomes through a noncompetitive mechanism of action. Their IC50 were 3.25, 2.27, and 4.32 μM, respectively. Dihydrocodeine, acetyldihydrocodeine, and lauroylcodeine were ineffective. In all the experimental circumstances M6G was undetectable in the incubation medium. In primary hepatocyte cultures codeine only inhibited M3G formation, but with a lower efficacy than that observed with microsomes (IC50 20.91 vs 4.32 μM). Preliminary results show that at micromolar concentrations codeine derivatives exhibit a low rate of affinity for μ opiate receptors. In conclusion, acetyl and pivaloyl derivatives of codeine noncompetitively inhibit liver glucuronidation of morphine interacting with microsomes. This study further strengths the notion that phenanthrenic opioids can modulate morphine glucuronidation independently from their effects on μ opiate receptors. |
| Databáze: | OpenAIRE |
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