Role of Organic Anion-Transporting Polypeptides for Cellular Mesalazine (5-Aminosalicylic Acid) Uptake

Abstract

ABSTRACT:The therapeutic effects and metabolism of mesalazine (5-aminosalicylic acid) in patients with inflammatory bowel disease require intracellular accumulation of the drug in intestinal epithelial cells and hepatocytes. The molecular mechanisms of mesalazine uptake into cells have not been characterized so far. Using human embryonic kidney cells stably expressing uptake transporters of the organic anion-transporting polypeptide (OATP) family, which are expressed in human intestine and/or liver, we found that mesalazine uptake is mediated by OATP1B1, OATP1B3, and OATP2B1 but not by OATP1A2 and OATP4A1. Moreover, genetic variations (*1b, *5, *15) in the SLCO1B1 gene encoding OATP1B1 reduced the K m value for mesalazine uptake from 55.1 to 16.3, 24.3, and 32.4 M, respectively, and the respective V max values. Finally, budesonide, cyclosporine, and rifampin were identified as inhibitors of OATP1B1-, OATP1B3-, and OATP2B1-meditated mesalazine uptake. These in vitro data indicate that OATP-mediated uptake and its modification by genetic factors and comedications may play a role for mesalazine effects.

Effects of Selected OATP and/or ABC Transporter Inhibitors on the Brain and Whole-Body Distribution of Glyburide

“…Our study illustrates how GLB plasma pharmacokinetics and distribution are largely governed by OATP transporters. RFA and CsA have a more pronounced inhibitory effect on OATP1A2, OATP1B1, and OATP1B3 than on OATP2B1 (13,(41)(42)(43)(44). In the present study, the organs in which […”

In vitro drug–drug interactions of budesonide: inhibition and induction of transporters and cytochrome P450 enzymes

“…Konig et al (2011) reported the inhibition of OATP1B1-and 1B3-mediated mesalazine uptake by budesonide in transporter-transfected human embryonic kidney cells; however, the budesonide concentrations tested in that study (10 mM and 100 mM) were much higher than those used here (0.002, 0.2 and 2 mM). Clinical DDI studies with budesonide are therefore considered not to be required based on clinically relevant concentrations.…”

Transintestinal transport mechanisms of 5-aminosalicylic acid (in situ rat intestine perfusion, Caco-2 cells) and Biopharmaceutics Classification System

“…In the dose of 10 and 100 µmol/l AP-BL percent transport was higher (vs. BL-AP), which might suggest a carrier-mediated transepithelial transport of the proper 5-ASA. König et al (2011) demonstrated that intracellular accumulation of 5-ASA (20 µmol/l) is mediated by members of the OATP uptake transporter family. Domination of the passive transport in the higher doses is probable as the percent transport of the proper 5-ASA was almost the same in AP-BL and BL-AP direction.…”

“…And also Xin et al (2006) concluded in their study that the intestinal secretion of 5-ASA observed in vivo is unlikely to be mediated by the efflux transporters P-glycoprotein (P-gp) or multidrug resistance-associated protein 2 (MRP2). The involvement of organic anion transporting polypeptide (OATP) family in the transport mechanism of 5-ASA was suggested by König et al (2011).…”