Species Difference in the Effect of Grapefruit Juice on Intestinal Absorption of Talinolol between Human and Rat

Abstract

Bioavailability of talinolol, a ␤ 1 -adrenergic receptor antagonist, was enhanced by coadministration with grapefruit juice (GFJ) in rats, whereas GFJ ingestion markedly reduced the absorption of talinolol in humans. Because our recent study indicated that the inhibitory effect of GFJ on organic anion-transporting polypeptide (Oatp)-and P-gp-mediated talinolol absorption depends on the concentration of naringin in ingested GFJ, the apparent inconsistent findings may be explained by the species difference in the affinity of naringin for OATP/Oatp and P-gp multidrug resistance 1 (MDR1/Mdr1) between humans and rats. Although human MDR1-mediated talinolol transport was not inhibited by 2000 M naringin, naringin inhibited human OATP1A2-, rat Oatp1a5-, and rat Mdr1a-mediated talinolol transport with IC 50 values of 343, 12.7, and 604 M, respectively, in LLC-PK1 cell and Xenopus laevis oocyte systems.Because the naringin concentration in commercially prepared GFJ was found to be approximately 1200 M, these results suggested that GFJ would reduce the intestinal absorption of talinolol through inhibition of OATP1A2-mediated talinolol uptake in humans, whereas an increase of talinolol absorption is mainly through inhibition of Mdr1a-mediated efflux in rats. The rat intestinal permeability of talinolol measured by the in situ closed loop method was indeed significantly increased in the presence of GFJ, whereas a significant decrease was observed with 6-fold diluted GFJ, in which the naringin concentration was approximately 200 M. The present study indicated that the species difference in the effect of GFJ on intestinal absorption of talinolol between humans and rats may be due to differences in the affinity of naringin for OATP/Oatp and MDR1/Mdr1 transporters between the two species.

The Role of a Basolateral Transporter in Rosuvastatin Transport and Its Interplay with Apical Breast Cancer Resistance Protein in Polarized Cell Monolayer Systems

“…Furthermore, in contrast to MDCK cells, Caco-2 failed to sort recombinant NTCP-GFP protein into polarized surface expression on the plasma membrane and showed no polarity of taurocholate uptake (Sun et al, 2001), thus suggesting a lack of meaningful NTCP protein expression and function in Caco-2 systems. Both OATP1A2 and OATP2B1 are expressed at the apical membrane of enterocytes or Caco-2 cells (Sai et al, 2006;Glaeser et al, 2007), where they can contribute to the absorption of drugs such as statins, fexofenadine, levofloxacin, methotrexate, and talinolol (Badagnani et al, 2006;Ho et al, 2006;Maeda et al, 2007;Kitamura et al, 2008;Shirasaka et al, 2010;Ming et al, 2011). For the aforementioned reasons, it is highly unlikely that OATP1B1, OATP1B3, OATP2B1, OATP1A2, or NTCP could be involved in the basolateral uptake of rosuvastatin in Caco-2 cells.…”

Interactions of Green Tea Catechins with Organic Anion-Transporting Polypeptides

“…Given that OATP1A2 is expressed in enterocytes, our results suggest that OATP1A2 could be involved in the absorption of ECG and EGCG from the gut. Furthermore, given that OATP1A2 can transport numerous drugs including fexofenadine (Cvetkovic et al, 1999), several antibiotics such as levofloxacin (Maeda et al, 2007), methotrexate (Badagnani et al, 2006), statins (Fujino et al, 2005;Ho et al, 2006), and talinolol (Shirasaka et al, 2010), there is the potential for fooddrug interactions such as the ones described for fruit juices (Dresser et al, 2002;Lilja et al, 2004;Greenblatt, 2009) in patients that complement their prescription drugs with over-the-counter green tea supplements. A similar danger may exist for OATP1B3.…”

“…Both OATP1A2 and OATP2B1 are expressed at the apical membrane of enterocytes (Kobayashi et al, 2003;Glaeser et al, 2007) where they can contribute to the absorption of drugs such as statins, sartans, fexofenadine, talinolol, and methotrexate (Shimizu et al, 2005;Badagnani et al, 2006;Ho et al, 2006;Kitamura et al, 2008;Shirasaka et al, 2010). In the liver, OATP1B1, OATP1B3, and OATP2B1 are expressed at the basolateral membrane of hepatocytes (Abe et al, 1999;König et al, 2000;Kullak-Ublick et al, 2001).…”

Long-Lasting Inhibitory Effect of Apple and Orange Juices, but Not Grapefruit Juice, on OATP2B1-Mediated Drug Absorption

“…On the other hand, recent investigations have demonstrated that GFJ also decreases the bioavailability of a variety of clinically used drugs (Dresser et al, 2002;Schwarz et al, 2005;Bailey et al, 2007;Shirasaka et al, 2009Shirasaka et al, , 2010a. One of the putative mechanisms underlying this GFJ-drug interaction is thought to be a reduction in absorptive transport of drugs in small intestine owing to inhibition of organic anion transporting polypeptide (OATP) by GFJ and its components (Dresser et al, 2002;Bailey et al, 2007;Shirasaka et al, 2009Shirasaka et al, , 2010a.…”