Synthesis and evaluation of nevirapine analogs to study the metabolic activation of nevirapine
| Autor: | Kyoko Takahashi, Tomoyuki Ohe, Daisuke Yasuda, Shigeo Nakamura, Yasuhiro Tateishi, Tadahiko Mashino, Yasuhiro Kazuki |
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| Rok vydání: | 2020 |
| Předmět: |
Nevirapine
Cell Survival Pharmaceutical Science Pharmacology 030226 pharmacology & pharmacy Structure-Activity Relationship 03 medical and health sciences Pyrimidine analogue 0302 clinical medicine immune system diseases Oxidoreductase Tumor Cells Cultured medicine Humans Pharmacology (medical) Cytotoxicity 030304 developmental biology chemistry.chemical_classification Liver injury 0303 health sciences Dose-Response Relationship Drug Molecular Structure CYP3A4 biology Reverse-transcriptase inhibitor virus diseases Cytochrome P450 Hep G2 Cells medicine.disease chemistry Microsomes Liver biology.protein Reverse Transcriptase Inhibitors medicine.drug |
| Zdroj: | Drug Metabolism and Pharmacokinetics. 35:238-243 |
| ISSN: | 1347-4367 |
| Popis: | Nevirapine (NVP) is widely used as a non-nucleoside reverse transcriptase inhibitor of HIV-1, however, it is associated with severe skin and liver injury. The mechanisms of these adverse reactions are not yet clear, but the metabolic activation of NVP is thought to be related to the injury process. Until now, several metabolic activation pathways of NVP have been reported. In this study, in order to identify the reactive metabolite of NVP mainly responsible for CYP inhibition and liver injury, we synthesized five NVP analogs designed to avoid the proposed bioactivation pathway and evaluated their metabolic stabilities, CYP3A4 time-dependent inhibitory activities, and cytotoxicity. As a result, only a pyrimidine analog of NVP, which could avoid the formation of a reactive epoxide intermediate, did not inhibit CYP3A4. Outside of this compound, the other synthesized compounds, which could avoid the generation of a reactive quinone-methide intermediate, inhibited CYP3A4 equal to or stronger than NVP. The pyrimidine analog of NVP did not induce cytotoxicity in HepG2 and transchromosomic HepG2 cells, expressing major four CYP enzymes and CYP oxidoreductase. These results indicated that the epoxide intermediate of NVP might play an important role in NVP-induced liver injury. |
| Databáze: | OpenAIRE |
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