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.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
OATP1B1 and OATP1B3 may have contributed to the hepatic uptake of nateglinide, but the possibility of drug-drug interactions appeared to be low.
Drug Metabolism and Pharmacokinetics, Development Research Laboratories, Research Center, Ajinomoto Pharmaceuticals Co., Ltd., Kawasaki, Japan. toshiyuki_takanohash@ajinomoto.com
Toshiyuki
T
Takanohashi
Satoru
S
Kubo
Harumi
H
Arisaka
Kenji
K
Shinkai
Kazuyuki
K
Ubukata
D001692:Biological Transport; D002478:Cells, Cultured; D003510:Cyclohexanes / Q000493:pharmacokinetics*; D004347:Drug Interactions; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics*; D027381:Liver-Specific Organic Anion Transporter 1; D008962:Models, Theoretical; D000077715:Nateglinide; D027361:Organic Anion Transporters / Q000502:physiology*; D029362:Organic Anion Transporters, Sodium-Independent / Q000502:physiology*; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013997:Time Factors
D003510:Cyclohexanes; D007004:Hypoglycemic Agents; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D000077715:Nateglinide; D010649:Phenylalanine