Abstract
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 BEHTM 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.
Highlights
Hepatitis C virus (HCV) is considered as the main cause of chronic hepatitis which mostly progress to liver cirrhosis, and probably hepatocellular carcinoma
TAM has been considered as a prodrug which is activated inside the body by the CYP450 enzymes; CYP2D6, CYP2C9, and CYP3A4; to active metabolites, including 4-hydroxy tamoxifen (TOH)[13]
The various cytochrome P450 (CYP)-450 enzymes (CYP2D6, CYP2C9, CYP3A4) that are involved in TAM metabolism can be altered by many factors either due to variation in pharmacogenesis or due to induction/inhibition by various pharmaceutical drugs or natural products with a possible alteration in TAM bioavailability[15,16]
Summary
Hepatitis C virus (HCV) is considered as the main cause of chronic hepatitis which mostly progress to liver cirrhosis, and probably hepatocellular carcinoma. The emergence of direct-acting antiviral agents (DAAs) has greatly influenced the treatment of chronic HCV infections. These DAAs target different stages in the virus life cycle. Mechanistic data showed that DAAs are substrates/modulators of liver enzymes and/or active transporters which contribute largely to drug-drug interactions (DDIs). Most of the studied flavonoids resulted in a significant increase in the bioavailability of TAM with a significant alteration in metabolite (TOH)/parent (TAM) ratio suggesting flavonoid-related effect on the metabolism of TAM to TOH17–21. TAM and TOH have the potential to inhibit P-gp mediated drug transport as well as CYP3A-mediated metabolism[28]. They could affect the PK of co-administered drugs. Our research team has previously studied the PK interaction between TAM and the anticancer drug erlotinib (ERL)[29] where an increase in TAM Cmax with no significant increase in AUC, along with a decrease in AUC of ERL were recorded
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