title: Pivaloylcodeine, a new codeine derivative, for the inhibition of morphine glucuronidation. An in vitro study in the rat.
abstract: 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.
authors.affiliation: Department of Physiology and Pharmacology 'Vittorio Erspamer', Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Antonilli
authors.forename: Anna Rita
authors.initials: AR
authors.lastname: Togna
authors.forename: Giovanna
authors.initials: G
authors.lastname: Sabatini
authors.forename: Alessandro
authors.initials: A
authors.lastname: Venditti
authors.forename: Laura
authors.initials: L
authors.lastname: Guarcini
authors.forename: Giuseppina I
authors.initials: GI
authors.lastname: Togna
authors.forename: Rosario
authors.initials: R
authors.lastname: Nicoletti
authors.forename: Filomena
authors.initials: F
authors.lastname: Sanasi
authors.forename: Armandodoriano
authors.initials: A
authors.lastname: Bianco
authors.forename: Paolo
authors.initials: P
authors.lastname: Nencini
mesh_terms: D000818:Animals; D003061:Codeine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D022781:Hepatocytes / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D009022:Morphine Derivatives / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D009022:Morphine Derivatives; C000591644:pivaloylcodeine; C035349:morphine-6-glucuronide; C018108:morphine-3-glucuronide; D003061:Codeine
keywords: Acetylcodeine; Codeine; Glucuronidation; Liver microsomes; Morphine-3-glucuronide; Pivaloylcodeine