Mechanism of the stationary canalicular excretion of tributylmethyl ammonium in rats with a CCl4-induced acute hepatic injury.
The in vivo canalicular excretion clearance of tributylmethyl ammonium (TBuMA), a P-glycoprotein (P-gp) substrate, was previously reported to be unaffected by the induction of an experimental hepatic injury (EHI) by CCl(4) despite the increased expression of P-gp in the EHI liver. The objective of this study, therefore, was to elucidate the mechanism for the unchanged canalicular excretion clearance of TBuMA in EHI rats. TBuMA uptake was increased in cLPM vesicles from EHI rats compared with that from control rats. The total bile salt concentration in EHI liver was significantly reduced compared with that in a control liver. Because, in our previous studies, the uptake of TBuMA by cLPM vesicles was found to be significantly enhanced in the presence of bile salts, the reduction in bile salt levels in the EHI liver may be related to the unaltered TBuMA clearance. Despite the fact that the uptake of TBuMA by cLPM vesicles was increased by the addition of an EHI liver extract, the extent of the increase was comparatively less compared to the addition of a control liver extract. The in vivo excretion clearance of TBuMA was increased in a taurodeoxycholate dose-dependent manner in EHI rats. These observations suggest, therefore, that despite the induction of P-gp expression by the EHI, the in vivo canalicular excretion clearance of TBuMA remains unaltered as the result of an offset by reduced levels of bile salt(s).
Choi
Min-Koo
MK
Department of Pharmaceutics, College of Pharmacy, Seoul National University, San 56-1, Shinlim-dong, Kwanak-gu, Seoul 151-742, Korea.
Song
Im-Sook
IS
Park
So-Ra
SR
Hong
Soon-Sun
SS
Kim
Dae-Duk
DD
Chung
Suk-Jae
SJ
Shim
Chang-Koo
CK
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D001647:Bile Acids and Salts / Q000032:analysis; D001648:Bile Canaliculi / Q000378:metabolism*; D002251:Carbon Tetrachloride; D008099:Liver / Q000293:injuries* / Q000378:metabolism*; D008297:Male; D000644:Quaternary Ammonium Compounds / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001647:Bile Acids and Salts; D000644:Quaternary Ammonium Compounds; C043902:tri-n-butylmethylammonium; D002251:Carbon Tetrachloride