Hepatobiliary excretion of tributylmethylamonium in rats with lipopolysaccharide-induced acute inflammation.
The alteration in the pharmacokinetic behaviors of organic cations (OCs) in rats during acute inflammation (Al) was investigated. Al was induced by an intraperitoneal injection of lipopolysaccharide (LPS, 5 mg/kg) 24 hr prior to the start of pharmacokinetic studies. Tributylmethylammonium (TBuMA) was selected as a model OC since it is largely excreted into bile, and is neither metabolized nor binds to proteins in the body. When TBuMA was administered intravenously to Al rats at a dose of 6.6 micromole/kg, the AUC was increased, while biliary excretion (i.e., cumulative amount and apparent clearance) was decreased compared to normal rats. When TBuMA was administered intravenously to Al rats at a constant rate (i.e., a bolus injection at a dose of 1.5 micromole/kg followed by a constant infusion at a rate of 1.5 micromole/kg/hr for 165 min), steady-state concentrations of plasma and liver concentrations of TBuMA were increased significantly, while in vivo hepatic uptake (amount) and canalicular excretion (clearance) were decreased. These results are consistent with a hypothesis in which both the sinusoidal uptake of TBuMA into hepatocytes via the OCT1 and the canalicular excretion of the compound from hepatocytes via the P-gp are decreased by LPS-induced Al.
Lee
In-Kyung
IK
Department of Pharmaceutics, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
Lee
Young-Mi
YM
Song
Im-Sook
IS
Chung
Suk-Jae
SJ
Kim
Sang-Geon
SG
Lee
Myung-Gull
MG
Shim
Chang-Koo
CK
D000208:Acute Disease; D000818:Animals; D001652:Bile Ducts / Q000187:drug effects / Q000378:metabolism*; D007249:Inflammation / Q000209:etiology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D000644:Quaternary Ammonium Compounds / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
D008070:Lipopolysaccharides; D000644:Quaternary Ammonium Compounds; C043902:tri-n-butylmethylammonium