|
KMID : 0369819960260010033
|
|
Jorunal of Korean Pharmaceutical Sciences
1996 Volume.26 No. 1 p.33 ~ p.42
|
|
|
Effect of Phenobarbital on the Hepatic Clearance of Diltiazem in Isolated Rat Hepatocytes
|
|
이용복/Lee YB
오준교/고익배/Oh JK/Koh IB
|
|
|
Abstract
|
|
|
|
In order to study the effect of phenobarbital(PB) on the hepatic transport of diltiazem(DTZ), Ca2+ channel blocker, we used isolated hepatocytes of rat which was intraperitoneally pretreated with phenobarbital sodium(75 mg/kg) for four days once a day. For the isolation of rat liver cells, a modification of the two step procedure of Seglen was used. DTZ was dissolved in incubation buffer to the final DTZ concentrations of 200, 400, 600, 800 and 1000 ng/ml in order to elucidate the uptake characteristics of DTZ by hepatocytes. Reactions were stopped at 10, 20, 30, 45, 60, 90, 120 and 300 sec. The initial velocity was determined by disappearance of diltiazem in the hepatocyte suspension. On the other hand, to determine the effect of PB on the in vitro hepatic intrinsic clearance of DTZ we obtained the metabolism rates of DTZ in the control and the PB-pretreated rat hepatocyte at various time intervals. According to pretreatment with PB, the size of hepatocyte and the amount of protein per 106 cells were significantly (p<0.01) increased from 26.92±0.1364m to 35.31±1.00m and from 468±6.5μg/106 cells to 628.8±12.1μg/106 cells, respectively. In the case or hepatic uptake of diltiazem, Km was not different in the normalization by cell numbers and increased from 2.90μMto13.89μM in the normalization by protein amount. Vmax was increased regardless of normalization by protein amount and cell numbers, from 1.21μmole/min?mgproteinto3.96μmole/min?mgproteinandfrom2.38μmole/min?106cellsto2.83μmole/min?106cells, respectively. The in vitro hepatic intrinsic clearance of DTZ was significantly (p<0.01) increased from 0.640±0.038ml/mim?106cellsto2.385±0.212ml/min?106cells due to PB-pretreatment. These results suggest that the uptake of DTZ by hepatocyte is extremely fast and PB enhances the hepatic intrinsic metabolic clearance of DTZ.
|
|
|
KEYWORD
|
|
|
Diltiazem, Phenobarbital pretreatment, Hepatic uptake, Hepatic intrinsic clearance, Rat hepatocytes
|
|
|
FullTexts / Linksout information
|
|
|
|
|
|
Listed journal information
|
|
|
|