The new acyl‐CoA cholesterol acyltransferase inhibitor SMP‐797 does not interact with statins via OATP1B1 in human cryopreserved hepatocytes and oocytes expressing systems

Abstract

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.

Inhibition of the organic anion‐transporting polypeptide 1B1 by quercetin: an in vitro and in vivo assessment

“…OATP1B1‐mediated uptake of E3S is known to be biphasic with K m values for high and low affinity components of 67.5 n m and 7 µ m , respectively [22]. Because pravastatin mainly shares the high affinity site with E3S on OATP1B1 [23], so we set the concentration of [ 3 H]‐E3S at 50 n m (a value lower than 67.6 n m ) for estimating the effect of quercetin on the high affinity binding site. Our data showed that quercetin inhibited the OATP1B1‐mediated [ 3 H]‐E3S uptake in a competitive manner with a K i value of 17.9 ± 4.6 µ m .…”

Comparative hepatotoxicity of a herbicide, epyrifenacil, in humans and rodents by comparing the dynamics and kinetics of its causal metabolite

“…A hepatocyte uptake assay was conducted using the previously described method with modifications. 21,22) In short, the cells were incubated in a medium containing radiolabeled S-3100-CA and finally separated on the basis of difference in specific gravity using an oil layer of intermediate density. An aliquot (100 µL) of each suspension of cryopreserved primary hepatocytes (2.0×10 6 cells/mL) was pre-incubated for 5 min at 37°C or 4°C (on ice).…”

Implications of the Dominant Role of Transporters in Drug Uptake by Cells (Supplementary Material)

“…Understanding that coadministration of fludarabine and imatinib was likely in the treatment of chronic myeloid leukaemia, and knowing that fludarabine is absorbed by the equilibrative nucleoside transporters (ENT1 and ENT2), Woodahl et al [93] identified a transporter-mediated interaction in isolated lymphocytes. Similarly, Kitamura et al [94] speculated that a drug interaction might occur at OATP1B1 between the statins that are known substrates and the drug SMP-797 (an acyl-CoA cholesterol acyltransferase inhibitor), which was likely to be co-administered. Although screens in hepatocytes and transfected oocytes did not detect any interaction, this demonstrates the utility of transporter screens in exploring transporter-mediated interactions prior to administration.…”