Publication
High resolution mass spectrometry-based methodologies for identification of Etravirine bioactivation to reactive metabolites: In vitro and in vivo approaches.
| dc.contributor.author | Godinho, A | |
| dc.contributor.author | Martins, I | |
| dc.contributor.author | Nunes, J | |
| dc.contributor.author | Charneira, C | |
| dc.contributor.author | Grilo, J | |
| dc.contributor.author | Silva, D | |
| dc.contributor.author | Pereira, S | |
| dc.contributor.author | Soto, K, et al. | |
| dc.date.accessioned | 2019-02-18T16:53:13Z | |
| dc.date.available | 2019-02-18T16:53:13Z | |
| dc.date.issued | 2018 | |
| dc.description.abstract | Drug bioactivation to reactive metabolites capable of covalent adduct formation with bionucleophiles is a major cause of drug-induced adverse reactions. Therefore, elucidation of reactive metabolites is essential to unravel the toxicity mechanisms induced by drugs and thereby identify patient subgroups at higher risk. Etravirine (ETR) was the first second-generation Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) to be approved, as a therapeutic option for HIV-infected patients who developed resistance to the first-generation NNRTIs. Additionally, ETR came into market aiming to overcome some adverse effects associated with the previously used efavirenz (neurotoxicity) and nevirapine (hepatotoxicity) therapies. Nonetheless, post-marketing reports of severe ETR-induced skin rash and hypersensitivity reactions have prompted the U.S. FDA to issue a safety alert on ETR. Taking into consideration that ETR usage may increase in the near future, due to the possible use of the drug for coinfection with malaria and HIV, the development of reliable prognostic tools for early risk/benefit estimations is urgent. In the current study, high resolution mass spectrometry-based methodologies were integrated with MS3 experiments for the identification of reactive ETR metabolites/adducts: 1) in vitro incubation of the drug with human and rat liver S9 fractions in the presence of Phase I and II co-factors, including glutathione, as a trapping bionucleophile; and 2) in vivo, using urine samples from HIV-infected patients on ETR therapy. We obtained evidence for multiple bioactivation pathways leading to the formation of covalent adducts with glutathione and N-acetyl-L-cysteine. These results suggest that similar reactions may occur with cysteine residues of proteins, supporting a role for ETR bioactivation in the onset of the toxic effects elicited by the drug. Additionally, ETR metabolites stemming from amine oxidation, with potential toxicological significance, were identified in vitro and in vivo. Also noteworthy is the fact that new metabolic conjugation pathways of glucuronide metabolites were demonstrated for the first time, raising questions about their potential toxicological implications. In conclusion, these results represent not only a contribution towards the elucidation of new metabolic pathways of drugs in general but also an important step towards the elucidation of potentially toxic ETR pathways, whose understanding may be crucial for reliable risk/benefit estimations of ETR-based regimens. | pt_PT |
| dc.description.version | info:eu-repo/semantics/publishedVersion | pt_PT |
| dc.identifier.citation | Eur J Pharm Sci. 2018 Jul 1;119:70-82 | pt_PT |
| dc.identifier.doi | 10.1016/j.ejps.2018.03.026 | pt_PT |
| dc.identifier.issn | 1879-0720 | |
| dc.identifier.uri | http://hdl.handle.net/10400.10/2123 | |
| dc.language.iso | eng | pt_PT |
| dc.peerreviewed | yes | pt_PT |
| dc.publisher | Elsevier | pt_PT |
| dc.subject | HIV infections | pt_PT |
| dc.subject | Spectrometry mass ionization electrospray ionization | pt_PT |
| dc.subject | Etravirine | pt_PT |
| dc.title | High resolution mass spectrometry-based methodologies for identification of Etravirine bioactivation to reactive metabolites: In vitro and in vivo approaches. | pt_PT |
| dc.type | journal article | |
| dspace.entity.type | Publication | |
| oaire.citation.conferencePlace | Amsterdam | pt_PT |
| oaire.citation.endPage | 82 | pt_PT |
| oaire.citation.startPage | 70 | pt_PT |
| oaire.citation.title | European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences. | pt_PT |
| oaire.citation.volume | 119 | pt_PT |
| rcaap.rights | closedAccess | pt_PT |
| rcaap.type | article | pt_PT |