Investigation of the effect of grapefruit juice on the absorption and permeability of statins

The aim of this study is to examine the intestinal absorption of four model substances (atorvastatin, pravastatin, simvastatin, lovastatin) selected from the statins, using both the Caco-2 cell line and the in situ intestinal perfusion technique. Primarily, equilibrium solubility experiments were performed to determine the solubility of selected statins. The grapefruit juice component naringin, as well as specific inhibitors, was used to evaluate the effect of intestinal transporters and metabolizing enzymes on the absorption and permeability of statins. Since atorvastatin is a substrate of CYP3A4, ketoconazole was used as a specific inhibitor; rifampin was chosen because pravastatin is an OATP substrate; and elacridar was utilized because simvastatin and lovastatin are P-gp substrates. In cell culture studies, the apparent permeability (Papp) values of active substances were determined and compared separately in the presence and absence of specific inhibitors or naringin. In in situ perfusion studies, the ileum was perfused with a solution containing only the active substance, and then with a solution containing the active substance and inhibitor or naringin. Permeability (Peff) values were calculated and compared. The amounts of active substances in the samples obtained from all studies were determined using validated HPLC methods. The solubility of the active substances was found to be low for atorvastatin, simvastatin and lovastatin, and high for pravastatin in accordance with literature. According to Caco-2 permeability results, while the permeability of atorvastatin did not change significantly in the presence of naringin, it decreased significantly (p=0.0142) in the presence of ketoconazole. The permeability of pravastatin increased significantly in the presence of naringin (p=0.0148) and rifampin (p=0.0089). The permeability of simvastatin through Caco-2 cells decreased significantly in the presence of naringin and elacridar (p<0.0001). According to intestinal perfusion results, the permeability of atorvastatin decreased in the presence of naringin (p = 0.0009) and ketoconazole (p=0.0038). While the permeability of pravastatin did not change significantly in the presence of rifampin, it decreased with naringin (p<0.0001). Findings from this study support that naringin has similar effects to specific inhibitors.