Effect of Atorvastatin on Single Oral Pharmacokinetics and Safety of Daclatasvir in Rats: Emphasis on P-glycoprotein and Cytochrome P450

Objective: This study aimed to investigate the effect of atorvastatin on daclatasvir oral pharmacokinetics and safety and assess the possible underlining mechanisms by targeting P-glycoprotein (P-gp) and cytochrome P450 (CYP3A4). Methods: The transport of daclatasvir, as well as the standard rhodamine 123 by P-gp across the rat intestine, was studied in vitro using the non-everted sac method. To assess the pharmacokinetic profile of daclatasvir in vivo, rats were divided into three groups receiving either saline, standard P-gp inhibitor verapamil (25 mg/kg), or atorvastatin (10 mg/kg), 2 hrs prior to a single dose of daclatasvir (7 mg/kg). In addition, the markers of liver and kidney functions and muscle rhabdomyolysis were assessed. Further, histopathological examination of liver and kidney tissue and assessment of CYP3A4 level was done. Results: The inhibitory effect of atorvastatin on Pgp activity and expression was manifested by increased serosal transport of the standard rhodamine 123, as well as daclatasvir. In vivo, Cmax (peak plasma concentration) and area under the curve (AUC (0-t)) of daclatasvir after atorvastatin treatment increased compared to the vehicle group but not in a significant manner. On the other hand, atorvastatin caused a significant increase in the clearance of daclatasvir. Concomitant administration of atorvastatin with daclatasvir significantly decreased CYP3A4 content compared to the control group. The combination also showed increased liver enzymes and some pathological alterations in the liver. Conclusion: Atorvastatin has a significant effect on P-gp mediated intestinal transport of daclatasvir; however, it did not affect the systemic bioavailability of a single oral dose of daclatasvir.