الفهرس 
HCV Epidemiology in EgyptOnly 14 pages are availabe for public view
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Abstract
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Summary:
Daclatasvir (DCV) is the first-in-class HCV NS5A inhibitor that has anti-viral effect across multiple HCV genotypes. Many Studies showed that DCV is a substrate of efflux transporters including P-gp. The major route of elimination of DCV is via CYP3A4-mediated metabolism and P-glycoprotein (P-gp) excretion and intestinal secretion.
It was proved that the use of statins improved the Sustained virological response (SVR) rates to antiviral therapy, decreased progression of liver fibrosis and decreased incidence of HCC among HCV patients. Atorvastatin is both substrate and inhibitor of P-gp. P-gp can potentially decrease the absorption and oral bioavailability and reduce the retention time of many drugs including DAAs and thus the use of P-gp modulators is a source of DDIs.
This has directed this research towards testing the pharmacokinetic interaction between atorvastatin and the direct acting antiviral drug daclatasvir, and the possible underlying mechanism through targeting P-gp and CYP 3A4. In addition, a possible hepatic or nephrotoxicity resulting from this interaction were also evaluated. The following experiments were carried out:
1- Experiment 1: Assessment of Daclatasvir transport across the intestine using an in-vitro non-everted sac method:
Summary and Conclusion
95
The transport of daclatasvir, as well as the standard rhodamine 123 across the rat intestine were studied in vitro using non-everted sac method. Also P-gp expression was assessed using RT-PCR analysis and western blotting of Pgp in rat intestine.
2- Experiment 2: Assessment of a single oral daclatasvir pharmacokinetics in-vivo:
To assess the pharmacokinetic profile of daclatasvir in vivo, rats were divided into three groups receiving either vehicle, standard Pgp inhibitor verapamil (25 mg/kg) or atorvastatin (10 mg/kg), 2hrs prior to single dose of daclatasvir (7 mg/kg). Moreover, Liver Samples were used for CYP 3A4 assay.
3- Experiment 3: Assessment of the safety of Atorvastatin and Daclatasvir combination:
Serum samples were analyzed biochemically for determination of liver, kidney and muscle rhabdomyolysis markers (AST, ALT, Urea, Creatinine, LDH, Total CK) in addition to histopathological examination.
Results from Experiment 1:
- The mucosal-to-serosal transport of rhodamine 123 was significantly increased by atorvastatin at all time intervals, compared to the control and verapamil groups.
- The mucosal-to-serosal transport of daclatasvir was increased by atorvastatin and verapamil more than its transport in vehicle group.
Summary and Conclusion
96
- Treatment by atorvastatin and verapamil Significantly decreased P-gp genetic and protein expression level as compared to vehicle control group.
Results from Experiment 2:
- Concomitant administration of atorvastatin with daclatasvir caused an increase in Cmax and AUC(0‐t) of daclatasvir compared to vehicle group but not in a significant manner at p < 0.05 level.
- A statistically significant increase in the clearence of daclatasvir was also obtained upon concomitant administration with atorvastatin and Verapamil in comparison to vehicle group.
- MRT (Mean residence time) and T1/2 (Half life) of Daclatasvir was significantly decreased upon concomitant administration with atorvastatin.
- Concomitant administration of atorvastatin with daclatasvir significantly decreased CYP 3A4 Enzyme content compared to the control group.
Results from Experiment 3:
- Statistically significant increase in serum levels AST and ALT was observed in atorvastatin group compared to control group.
- No statistically significant change was found in kidney markers.
- Regarding rhabdomyolsis markers, LDH level showed a significant increase in atorvastatin group compared to control group.
Summary and Conclusion
97
- Hispathological Examination revealed that: In liver: Verapamil group showed mild insignificant degenerative changes of hepatocytes in different hepatic zones. Atorvastatin group showed wide areas of diffuse vacuolar degeneration of hepatocytes with mild dilatation of hepatic blood vessels and focal areas of periportal inflammatory cells aggregation.
In Kidney: Both verapamil and atorvastatin groups showed widely congested intertubular as well as glomerular blood vessels with mild few tubular degenerative changes and focal peri-glomerular and perivascular mononuclear inflammatory cells infiltrations. However; the severity of infiltrates was lesser in the Atorvastatin group.
Conclusion:
Co-administration of atorvastatin with daclatasvir appear to have significant effect on P-gp mediated intestinal transport of daclatasvir. However, not all Drug-Drug interaction (DDI) that are predicted in-vitro will occur in-vivo. Although, a single dose of atorvastatin did not affect the systemic bioavailability of dalatasvir, concomitant use of daclatasvir with atorvastatin may require close monitoring for potential drug interactions and possible hepatic manifestations on the long-term intake. So, further evaluation of daclatasvir – atorvastatin for the potential DDI are warranted in clinical practice