Reversible time-dependent inhibition of cytochrome P450 enzymes by duloxetine and inertness of its thiophene ring towards bioactivation.
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Chan CY, New LS, Ho HK, Chan EC
Reversible time-dependent inhibition of cytochrome P450 enzymes by duloxetine and inertness of its thiophene ring towards bioactivation.
Toxicol Lett. 2011 Oct 30;206(3):314-24. doi: 10.1016/j.toxlet.2011.07.019. Epub 2011 Aug 5.
- PubMed ID
- 21839818 [ View in PubMed]
- Abstract
Duloxetine is a selective serotonin-norepinephrine reuptake inhibitor (SNRI) approved to treat major depressive disorder and diabetic peripheral neuropathic pain. It is known to cause hepatotoxicity, in some cases leading to death. It has been reported that duloxetine causes time-dependent inhibition (TDI) of CYP1A2, CYP2B6, CYP2C19 and CYP3A4/5; but the nature of these TDI (whether reversible or irreversible) is not known. Irreversible TDI can cause clinically significant drug-drug interactions and also immune-mediated hepatotoxicity. Structurally, duloxetine possesses several toxicophores, i.e. the naphthyl and thiophene rings. It has been reported that the naphthyl ring undergoes epoxidation and was subsequently adducted to glutathione, but bioactivation related to the thiophene ring has not been completely elucidated. In this paper, the potential of duloxetine in causing irreversible TDI and generating reactive metabolites was investigated. Human liver microsomal assays demonstrated that duloxetine did not cause irreversible TDI of CYP1A2, CYP2B6, CYP2D6, CYP2C19 and CYP3A4/5. Subsequently, reactive metabolite trapping assays using soft nucleophiles (glutathione and glutathione ethyl ester) revealed a previously reported adduct at the naphthyl ring of duloxetine but not at the thiophene ring. Trapping assays utilizing a hard nucleophile (semicarbazide) did not demonstrate adducts with the thiophene ring, indicating an absence of thiophene ring opening. The hepatotoxicity of duloxetine is possibly not related to the irreversible TDI of CYP450 or the bioactivation of its thiophene moiety, but might be due to the epoxidation of its naphthyl ring.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Duloxetine Cytochrome P450 1A2 Protein Humans UnknownSubstrateInhibitorDetails Duloxetine Cytochrome P450 2B6 Protein Humans UnknownInhibitorDetails Duloxetine Cytochrome P450 2C19 Protein Humans UnknownInhibitorDetails Duloxetine Cytochrome P450 3A4 Protein Humans UnknownInhibitorDetails