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Development and validation of UPLC-MS/MS method for studying the pharmacokinetic interaction of dasabuvir and tamoxifen, 4-hydroxytamoxifen in Wistar rats

Hepatitis C virus (HCV) is the main cause of chronic hepatitis and probably liver cirrhosis. Dasabuvir (DSV) is a direct-acting antiviral agent with efficiency in managing HCV. The anti-viral activity of the anti-estrogen drug tamoxifen (TAM) suggested the synergistic effect of DSV and TAM for block...

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Detalles Bibliográficos
Autores principales: Almomen, Aliyah, Maher, Hadir M., Alzoman, Nourah Z., Shehata, Shereen M., Al-taweel, Shorog M., Alanazi, Ashwaq A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044166/
https://www.ncbi.nlm.nih.gov/pubmed/32103133
http://dx.doi.org/10.1038/s41598-020-60613-2
Descripción
Sumario:Hepatitis C virus (HCV) is the main cause of chronic hepatitis and probably liver cirrhosis. Dasabuvir (DSV) is a direct-acting antiviral agent with efficiency in managing HCV. The anti-viral activity of the anti-estrogen drug tamoxifen (TAM) suggested the synergistic effect of DSV and TAM for blocking the replication of HCV. However, being substrates and inhibitors of efflux transporters (TAM inhibits P-gp, DSV inhibits P-gp and BCRP), there is a possibility for a pharmacokinetic (PK) drug-drug interaction. In this work, a new UPLC-MS/MS method was developed and validated for the simultaneous determination of TAM, its active metabolite 4-hydroxy tamoxifen (TOH), and DSV in rat plasma. The method was applied to investigate the PK interaction between DSV and TAM/TOH following the co-administration of DSV and TAM to Wistar rats. Chromatographic analysis was performed on Waters BEH(TM) C18 column using a mobile phase of acetonitrile/water containing 0.1% formic acid (80: 20, v/v). The method allowed the determination of concentration ranges 20–1000, 0.1–500, 0.5–500 ng/mL for DSV, TAM, and TOH, respectively. Unexpectedly, results revealed the absence of PK interactions between DSV and TAM/TOH, compared with their single administration, suggesting the safety of co-administering DSV/TAM as an anti-viral combination without the need of dosage adjustment.