Effect of a New Hepatoprotective Agent, YH-439, on the Hepatobiliary Transport of Organic Cations (OCs): Selective Inhibition of Sinusoidal OCs Uptake without Influencing Glucose Uptake and Canalicular OCs Excretion원문보기
The effect of a new hepatoprotective agent, YH-439, on the hepatobiliary transport of a model organic cation (OC), TBuMA (tributylmethylammonium), was investigated. The area under the plasma concentration-time curve (AUC) from time zero to 4 h following iv administration of TBuMA (6.6 $\mu$
The effect of a new hepatoprotective agent, YH-439, on the hepatobiliary transport of a model organic cation (OC), TBuMA (tributylmethylammonium), was investigated. The area under the plasma concentration-time curve (AUC) from time zero to 4 h following iv administration of TBuMA (6.6 $\mu$mol/kg) was increased significantly when YH-439 in corn oil (300 mg/kg) was orally administered to rats 24 h prior to the experiment. Nevertheless, the cumulative biliary excretion of TBuMA remained unchanged. As a consequence, the apparent biliary clearance ($CL_b$) of TBuMA was decreased significantly as a result of YH-439 pretreatment, consistent with the fact that the in vivo excretion clearance of TBuMA across the canalicular membrane ($CL_{exc}$) was not changed by the pretreatment. The in vitro uptake of TBuMA into isolated hepatocytes was decreased by one half by the pretreatment, owing to a decrease in the apparent V$_{max}$ and $CL_{linear}$, but the $K_m$ for the process remained constant. Most interestingly, however, the sinusoidal uptake of glucose, a nutrient, into hepatocytes was not influenced by the pretreatment, suggesting the YH-439 pretreatment specifically impaired the sinusoidal uptake of OCs. Thus, the OC-specific inhibition of hepatic uptake, without influencing the uptake of glucose, a nutrient, appeared to be associated with the hepatoprotective activity of YH-439.
The effect of a new hepatoprotective agent, YH-439, on the hepatobiliary transport of a model organic cation (OC), TBuMA (tributylmethylammonium), was investigated. The area under the plasma concentration-time curve (AUC) from time zero to 4 h following iv administration of TBuMA (6.6 $\mu$mol/kg) was increased significantly when YH-439 in corn oil (300 mg/kg) was orally administered to rats 24 h prior to the experiment. Nevertheless, the cumulative biliary excretion of TBuMA remained unchanged. As a consequence, the apparent biliary clearance ($CL_b$) of TBuMA was decreased significantly as a result of YH-439 pretreatment, consistent with the fact that the in vivo excretion clearance of TBuMA across the canalicular membrane ($CL_{exc}$) was not changed by the pretreatment. The in vitro uptake of TBuMA into isolated hepatocytes was decreased by one half by the pretreatment, owing to a decrease in the apparent V$_{max}$ and $CL_{linear}$, but the $K_m$ for the process remained constant. Most interestingly, however, the sinusoidal uptake of glucose, a nutrient, into hepatocytes was not influenced by the pretreatment, suggesting the YH-439 pretreatment specifically impaired the sinusoidal uptake of OCs. Thus, the OC-specific inhibition of hepatic uptake, without influencing the uptake of glucose, a nutrient, appeared to be associated with the hepatoprotective activity of YH-439.
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대상 데이터
Male Sprague-Dawley rats, 7 to 8 weeks of age, were used in the study. 丫너-439 pretreatment involved the oral administration of a suspension of YH-439 in corn oil (60 mg/mL) at a dose of 300 ㎎/㎏ for 3 consec니tive days.
데이터처리
, generally up to 1 min) of the plot, was then plotted against the initial concentration of the substrate in the medium. A nonlinear regression analysis was performed, to fit the plot to the following equation using WINNONLIN (version 1.0; SCI Software, Lexington, KY).
성능/효과
OCT1 on the sin니soidal membrane could repres으nt the transporter. A significant decrease in CL|inear by the pretreatment was also observed, suggesting that the non-saturable uptake, probably passive diff니sion, was also impaired by the pretreatment, However, the contribution of nonsaturable uptake to overall uptake was minimal, less than 10 %.
This suggests first that the effect of YH-439 is sinusoidal membrane-specific. The results of the in vitro hepatic uptake experiment revealed a decrease in Vmax rather than a change in Km, suggesting the decrease in the expression of relevant transporter, possibly OCT1. Contrary to the case for TBuMA, the uptake of glucose was not influeneed by the pretreatment, s니ggesting that the effect of YH-439 on the sinusoidal membrane is selective for specific transporters.
후속연구
, the protection of the liver from xenobiotics such as OCs through inhibiting their hepatic uptake, without impairing the hepatic uptake of nutrients such as glucose. The effects of YH-439 pretreatment on hepatic transporters other than OCT1 and GLUT2 in terms of expression and function await further investigation.
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