The new acyl-CoA cholesterol acyltransferase inhibitor SMP-797 does not interact with statins via OATP1B1 in human cryopreserved hepatocytes and oocytes expressing systems.
It is possible that SMP-797 will be administered frequently in combination with statins to hyperlipidemic patients. OATP1B1 is thought to be the major transporter that mediates the hepatic uptake of statins. This study investigated whether SMP-797 interacts with statins via OATP1B1 by two approaches. Firstly, the effects of SMP-797 on OATP1B1-mediated uptake of estrone-3-sulfate (ES) by human hepatocytes and by oocytes expressing OATP1B1 were examined. Since OATP1B1-mediated uptake of ES is known to be biphasic (high- and low-affinity sites), concentrations of [(3)H]ES were set lower than the respective K(m) values. Two representative statins were used to assure that statins share OATP1B1 with [(3)H]ES in this in vitro system. Rosuvastatin inhibited OATP1B1-mediated uptake of [(3)H]ES through both sites and pravastatin inhibited a high-affinity site. The inhibition by the positive control (cyclosporin A) was significant. Thus, it is considered that this system was applicable to examine drug-drug interaction with statins on OATP1B1-mediated uptake. In this condition, no apparent inhibition to each site by SMP-797 was observed up to a concentration 3,000-fold higher than the clinical level. Secondly, the uptake of [(14)C]SMP-797 by oocytes expressing OATP1B1 was examined and the activity was negligible. In conclusion, these data suggest that SMP-797 has little potential to interact with statins on OATP1B1.
Kitamura
Atsushi
A
Pharmacokinetics Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd, 1-98 Kasugade-naka 3-chome, Konohana-ku, Osaka, 554-0022, Japan. atsushi-kitamura@ds-pharma.co.jp
Imai
Satoki
S
Yabuki
Masashi
M
Komuro
Setsuko
S
D001667:Binding, Competitive; D001693:Biological Transport, Active; D015925:Cryopreservation; D016572:Cyclosporine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004970:Estrone / Q000031:analogs & derivatives / Q000378:metabolism; D005464:Fluorobenzenes / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism*; D066298:In Vitro Techniques; D027381:Liver-Specific Organic Anion Transporter 1; D009287:Naphthyridines / Q000494:pharmacology*; D009865:Oocytes / Q000378:metabolism; D027361:Organic Anion Transporters / Q000008:administration & dosage / Q000187:drug effects* / Q000378:metabolism; D017035:Pravastatin / Q000378:metabolism*; D011743:Pyrimidines / Q000378:metabolism*; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000378:metabolism*
D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027381:Liver-Specific Organic Anion Transporter 1; D009287:Naphthyridines; D027361:Organic Anion Transporters; D011743:Pyrimidines; C503999:SLCO1B1 protein, human; C508738:SMP-797; D013449:Sulfonamides; D004970:Estrone; D016572:Cyclosporine; D000068718:Rosuvastatin Calcium; D017035:Pravastatin; C017296:estrone sulfate