Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: KEGG:D05731 (Rimonabant)
 326 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Diabetes is one of the leading causes of painful neuropathy and to date, besides a tight glycemic control, a viable treatment for this complication is not available. Rimonabant is a selective cannabinoid CB(1) receptor antagonist that produces a significant increase in insulin sensitivity and a reduction of HbA(1c) in diabetic patients. This study aimed to investigate the therapeutic potential of rimonabant in relieving diabetes-induced neuropathic pain. The repeated treatment with rimonabant evoked a significant attenuation of mechanical allodynia in diabetic mice that was dose- and time-dependent. This effect occurred without alteration of hyperglycemia, but it was associated with significant effects on many key players in the pathogenesis of diabetic neuropathy. Metabolic changes induced by hyperglycemia lead to oxidative stress, deregulation of cytokine control and reduced production and transport of nerve growth factor (NGF), and all these factors contribute to neuropathic pain. Rimonabant treatment reduced oxidative stress in peripheral nerve, as revealed by the ability of the compound to counteract the reduced glutathione (GSH) depletion. The same repeated treatment inhibited tumor necrosis factor (TNFalpha) overproduction in the spinal cord and increased the NGF support. This rimonabant-induced improvement might favour the nerve regeneration; accordingly, the histological analysis of sciatic nerves showed a marked degeneration of myelinated fibers in diabetic mice, that was substantially reduced after rimonabant administration. These findings support the hypothesis that CB(1) antagonists would represent a new opportunity for diabetic patients, since currently there are no treatments for painful diabetic neuropathy other than treating the diabetic condition per se.
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PMID:Rimonabant, a cannabinoid CB1 receptor antagonist, attenuates mechanical allodynia and counteracts oxidative stress and nerve growth factor deficit in diabetic mice. 2039 4

In the present work, the characterization of the biotransformation and bioactivation pathways of the cannabinoid receptor 1 antagonist rimonabant (Acomplia) is described. Rimonabant was approved in Europe in 2006 for the treatment of obesity but was withdrawn in 2008 because of a significant drug-related risk of serious psychiatric disorders. The aim of the present work is to characterize the biotransformation and potential bioactivation pathways of rimonabant in vitro in human and rat liver microsomes. The observation of a major iminium ion metabolite led us to perform reactive metabolite trapping, covalent binding to proteins, and time-dependent inhibition of cytochrome P450 3A4 studies. The major biotransformation pathways were oxidative dehydrogenation of the piperidinyl ring to an iminium ion, hydroxylation of the 3 position of the piperidinyl ring, and cleavage of the amide linkage. In coincubations with potassium cyanide, three cyanide adducts were detected. A high level of covalent binding of rimonabant in human liver microsomes was observed (920 pmol equivalents/mg protein). In coincubations with potassium cyanide and methoxylamine, the covalent binding was reduced by approximately 40 and 30%, respectively, whereas GSH had no significant effect on covalent binding levels. Rimonabant was also found to inhibit cytochrome P450 3A4 irreversibly in a time-dependent manner. In view of these findings, it is noteworthy that, to date, no toxicity findings related to the formation of reactive metabolites from rimonabant have been reported.
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PMID:Bioactivation pathways of the cannabinoid receptor 1 antagonist rimonabant. 2173 82

The cannabinoid type 1 receptor (CB1r) antagonist rimonabant was approved in 2006 for the treatment of obesity but was withdrawn in 2008 due to serious drug-related psychiatric disorders. In vitro metabolism studies with rimonabant have revealed high levels of reactive metabolite formation, which resulted in irreversible time-dependent P450 3A4 inhibition and in covalent binding to microsomal proteins. In the present study, an in vitro approach has been used to explore whether metabolic bioactivation of rimonabant might result in cell toxicity. A panel of SV40-T-antigen-immortalized human liver derived (THLE) cells that had been transfected with vectors encoding various human cytochrome P450 enzymes (THLE-1A2, 2C9, 2C19, 2D6, and 3A4) or with an empty vector (THLE-Null) were exposed to rimonabant. Cell toxicity and covalent binding to cellular proteins were evaluated, as was metabolite formation. Rimonabant exhibited markedly potentiated dose and time dependent cytotoxicity to THLE-3A4 cells, compared to that of all other THLE cell lines. This was accompanied by high levels of covalent binding of [(14)C]-rimonabant to THLE-3A4 cell proteins (1433 pmol drug equivalents/mg protein) and the formation of several metabolites that were not generated by THLE-Null cells. These included N-aminopiperidine (NAP) and an iminium ion species. However, no toxicity was observed when THLE cells were incubated with NAP. Glutathione depletion did not alter the observed potent cell cytotoxicity of rimonabant to THLE-3A4 cells. Preincubation of THLE-3A4 cells with the cytochrome P450 3A4 inhibitor ritonavir blocked the selective toxicity of rimonabant to these cells. In addition, ritonavir pretreatment blocked the metabolism of the compound in the cells and thereby significantly decreased the covalent binding of [(14)C]-rimonabant to THLE-3A4 cell proteins. We conclude that the potent toxicity of rimonabant in THLE-3A4 cells occurs by a mechanistic sequence, which is initiated by cytochrome P450 3A4 mediated formation of a highly cytotoxic reactive iminium ion metabolite that binds covalently to cellular proteins.
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PMID:Bioactivation of the cannabinoid receptor antagonist rimonabant to a cytotoxic iminium ion metabolite. 2323 59