Differential Effect of Grapefruit Juice on Intestinal Absorption of Statins Due to Inhibition of Organic Anion Transporting Polypeptide and/or P-glycoprotein

The purpose of this study is to examine the contributions of organic anion transporting polypeptide (Oatp) and/or P-glycoprotein (P-gp) to grapefruit juice (GFJ) interaction with two statins, pravastatin and pitavastatin, which undergo negligible metabolism in rats. The two statins were found to be substrates of both Oatp1a5 and Oatp2b1, whereas pitavastatin, but not pravastatin, was a substrate of P-gp. The plasma concentration of pravastatin after oral administration was significantly decreased by GFJ and naringin, whereas that of pitavastatin was significantly increased. Naringin inhibited Oatp1a5- and Oatp2b1-mediated uptake of pravastatin and Oatp1a5-mediated, but not Oatp2b1-mediated, uptake of pitavastatin. Naringin also inhibited P-gp-mediated transport of pitavastatin. These results suggested that the decrease of pravastatin absorption in the presence of GFJ is due to the inhibitory effect of naringin on Oatp, whereas the increase of pitavastatin is due to the inhibition of P-gp. These observations are consistent with the results of in situ absorption studies. In conclusion, Oatp and/or P-gp contribute to the intestinal absorption of statins, and the differential effect of GFJ on pravastatin and pitavastatin absorption is at least partly accounted for by the different inhibitory effects of naringin on these transporters. © 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:3843–3853, 2011