Carrier-Mediated Active Transport of a Novel Thromboxane A₂ Receptor Antagonist [2-(4-Chlorophenylsulfonylaminomethyl)indan-5-yl]acetate (Z-335) into Rat Liver

Abstract

ABSTRACT:To elucidate the transport system by which [2-(4-chlorophenylsulfonylaminomethyl)indan-5-yl]acetate (Z-335) is taken up into the liver, we investigated the uptake characteristics of Z-335 in isolated rat hepatocytes. In addition, we estimated the hepatic uptake of Z-335 in intact rats under steady-state conditions and compared it with the in vitro uptake clearance. Uptake of Z-335 is highly concentrative (cell-to-medium concentration ratios were 21.2 at 0.5 min and 71.7 at 5 min), temperature-dependent, and sensitive to metabolic inhibitors, indicating that uptake is mediated by energydependent uphill transport. In the presence of metabolic inhibitors [carbonyl cyanide p-trifluoromethoxyphenylhydrazone and rotenone], uptake remained at 37 and 49% of the control value, respectively, suggesting that ATP-independent uptake contributes to the total uptake of Z-335. The concentration dependence of the initial uptake velocity indicated a two-component process, one saturable component, with a K m value of 45.6 M and a V max value of 4.1 nmol/min/mg of protein, and a nonspecific diffusion clearance, with a P dif value of 8.3 l/min/mg of protein. The contribution of the carrier-mediated uptake to the total uptake in a linear range was estimated as 91%. The in vivo hepatic intrinsic clearance (CL int, app ) was comparable with that in vitro uptake clearance (PS influx ) and indicated that the CL int, app of Z-335 at steady state is rate-limited by the uptake process. In conclusion, hepatic intrinsic clearance of Z-335 at steady state is rate-limited by the uptake process since Z-335 is efficiently taken up by an active transport mechanism, followed by metabolism or biliary excretion.

Mechanism of Hepatobiliary Transport of a Novel Thromboxane A2 Receptor Antagonist, [2-(4-Chlorophenylsulfonylaminomethyl)indan-5-yl]acetate (Z-335), and its Xenobiotic Taurine Conjugate (Z-335-Tau) in Rats

“…These results indicate that Z‐335 is mainly taken up into liver and is eliminated by metabolism or biliary excretion. We have recently demonstrated that Z‐335 is taken up into hepatocytes by the sodium‐independent active transport system, and that this uptake is inhibited by substrates of organic anion transporting polypeptides (oatps), such as estradiol 17β‐glucuronide, estrone 3‐sulfate, taurocholate, pravastatin, and bromosulfophthalein (BSP) 5. However, the mechanism for biliary excretion of Z‐335 is not clarified.…”