Investigation of the effect of verapamil on the regional absorption of sofosbuvir from rabbit intestine in situ.

Abstract

Purpose: Sofosbuvir, a nucleotide antiviral drug, is a Biopharmaceutics Classification System (BCS) class III prodrug suffering from limited intestinal absorption due to its high hydrophilicity and low intestinal permeability. This research aims to investigate the luminal stability of Sofosbuvir, the influence of anatomical site on its intestinal absorption and the effects of verapamil on such absorption.

Method: The study utilized in situ rabbit intestinal perfusion technique to examine absorption of Sofosbuvir from duodenum, jejunum, ileum and ascending colon. This was conducted both with and without verapamil.

Results: The luminal stability study showed that Sofosbuvir was subjected to premature degradation with varying fractions degraded from the different intestinal segments. The in situ perfusion data showed incomplete absorption of Sofosbuvir from small and large intestinal segments. The recorded values of the absorptive clearance per unit length (Pe.A/L) of Sofosbuvir were 0.026, 0.0075, 0.0026, & 0.054 ml/min.cm for duodenum, jejunum, ileum, and ascending colon, respectively. The Pe.A/L values were ordered as colon > duodenum > jejunum > ileum. This is the opposite rank of P-gp content in the different intestinal segments. The recorded values of the length required for complete Sofosbuvir absorption (L95%) were 29.58, 128.47, 949.2 and, 13.63 cm for duodenum, jejunum, ileum, and ascending colon, respectively. Co-perfusion with verapamil significantly increased Pe.A/L and reduced the L95% of Sofosbuvir from both jejunum and ileum (P-value < 0.05).

Conclusion: The results indicated that the absorptive clearance of Sofosbuvir was site dependent and associated with the content of P-glycoprotein, in addition to the expected drug interactions that can occur in polymedicated hepatitis C virus (HCV) infected patients.