Role of individual human cytochrome P450 enzymes in thein vitrometabolism of hydromorphone

Abstract

1. The aim was to identify the individual human cytochrome P450 (CYP) enzymes responsible for the in vitro N-demethylation of hydromorphone and to determine the potential effect of the inhibition of this metabolic pathway on the formation of other hydromorphone metabolites. 2. Hydromorphone was metabolized to norhydromorphone (apparent Km = 206 - 822 microM, Vmax = 104 - 834 pmol min(-1) mg(-1) protein) and dihydroisomorphine (apparent Km = 62 - 557 microM, Vmax = 17 - 122 pmol min(-1) mg(-1) protein) by human liver microsomes. 5. In pooled human liver microsomes, troleandomycin, ketoconazole and sulfaphenazole reduced norhydromorphone formation by an average of 45, 50 and 25%, respectively, whereas furafylline, quinidine and omeprazole had no effect. In an individual liver microsome sample with a high CYP3A protein content, troleandomycin and ketoconazole inhibited norhydromorphone formation by 80%. 5. The reduction in norhydromorphone formation by troleandomycin and ketoconazole was accompanied by a stimulation in dihydroisomorphine production. Recombinant CYP3A4, CYP3A5, CYP2C9 and CYP2D6, but not CYP1A2, catalysed norhydromorphone formation, whereas none of these enzymes was active in dihydroisomorphine formation. 6. In summary, CYP3A and, to a lesser extent, CYP2C9 catalysed hydromorphone N-demethylation in human liver microsomes. The inhibition of norhydromorphone formation by troleandomycin and ketoconazole resulted in a stimulation of microsomal dihydroisomorphine formation.

Effect of hydromorphone on ventilation in palliative care patients with dyspnea

“…Despite the fact that the N-demethylated (norhydromorphone) metabolite of hydromorphone is known to be formed, the specific cytochrome P450 (CYP) enzymes involved in catalyzing this metabolic pathway of hydromorphone have not been identified. Such information is important in predicting potential drug interactions with hydromorphone because patients taking opioids are often on multiple drug therapy [3]. The effectiveness and safety of nebulized hydromorphone in treating dyspnea has been reported in a few studies [14,15,25].…”

Capillary electrophoresis contributions to the hydromorphone metabolism in man

“…Among the phase II reactions, it is known that conjugation with glucuronic acid occurs with several HMOR metabolites [9,[12][13][14][15], and conjugation with sulfuric acid is reported to occur with HMOR [9]. The information regarding the metabolism of HMOR was gained from animal studies [12,13], via analysis of human body fluids, including urine [9,10,12], and in vitro incubations of HMOR with human liver microsomes or single enzymes [11].…”

“…1), a biotransformation that is catalyzed in vitro by the liver enzyme cytochrome P450 (CYP) system [9][10][11]. HMOR and NHMOR can be 6-ketoreduced to hydromorphol (HMOROL) and norhydromorphol (NHMOROL), respectively ( Fig.…”

“…Furthermore, a HPLC-MS method was employed for the study of the HMOR metabolism in vitro via incubations with human liver microsomes and single enzymes [11]. To the best of our knowledge, no CE-based method has ever been established for the determination of HMOR and its metabolites in a biological fluid.…”

Exploration of Catalytic Properties of CYP2D6 and CYP3A4 Through Metabolic Studies of Levorphanol and Levallorphan

“…The compound class used for this study was a family of morphinanyl opioid analgesics. These compounds are known substrates for both CYP2D6 and CYP3A4 that presumably adopt different orientations in the active sites of the two isoforms (Kirkwood et al, 1997;Yue and Sawe, 1997;von Moltke et al, 1998;Benetton et al, 2004;Hutchinson et al, 2004). CYP3A4 preferentially catalyzes the oxidative N-demethylation, and CYP2D6 catalyzes the oxidative O-demethylation of selected members of this class of compounds.…”