Journal of Pharmacy and Pharmacology 2012-02-01

Contribution of organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 to hepatic uptake of nateglinide, and the prediction of drug-drug interactions via these transporters.

Toshiyuki Takanohashi, Satoru Kubo, Harumi Arisaka, Kenji Shinkai, Kazuyuki Ubukata

Index: J. Pharm. Pharmacol. 64(2) , 199-206, (2012)

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Abstract

We have investigated the contributions of organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 to the hepatic uptake of nateglinide, and the possibility of drug-drug interactions via these transporters.Uptake studies using transporter-expressing HEK293 cells and cryopreserved human hepatocytes were performed to examine the contributions of each transporter. Inhibition studies using cryopreserved human hepatocytes were performed to examine the possibility of drug-drug interactions.The rate of saturable hepatic uptake of nateglinide using human hepatocytes was 47.6%. A certain increase in uptake was observed in the examination using transporter-expressing HEK293 cells, indicating contributions of OATP1B1 and OATP1B3 to hepatic nateglinide uptake. The 50% inhibitory concentration (IC50) values of nateglinide using cryopreserved human hepatocytes for uptake of estrone 3-sulfate (substrate of OATP1B1), and cholecystokinin octapeptide (substrate of OATP1B3) were 168 and 17.4 µmol/l, respectively. Moreover, ciclosporin inhibited saturable hepatic uptake of nateglinide with an IC50 value of 6.05 µmol/l. The calculated 1 + I(in,max,u) /IC50 values for inhibition of OATP1B1 and OATP1B3 by nateglinide, and the inhibition of saturable uptake of nateglinide by ciclosporin, were all close to 1, indicating a low clinical risk of drug-drug interaction with nateglinide taken up via OATP1B1 and OATP1B3.OATP1B1 and OATP1B3 may have contributed to the hepatic uptake of nateglinide, but the possibility of drug-drug interactions appeared to be low.© 2011 The Authors. JPP © 2011 Royal Pharmaceutical Society.