Hepatobiliary Excretion of Tributylmethylamonium in Rats with Lipopolysaccharide-Induced Acute Inflammation

• Published in: Archives of pharmacal research 2002, 25(6), , pp.969-972
• Main Authors: Lee, In-Kyung, Lee, Young-Mi, Song, Im-Sook, Chung, Suk-Jae, Kim, Sang-Geon, Lee, Myung-Gull, Shim, Chang-Koo
• Format: Article
• Language: Korean
• Subjects: 약학
• ISSN: 0253-6269; 1976-3786

The alteration in the pharmacokinetic behaviors of organic cations (OCs) in rats during acute inflammation (AI) was investigated. AI 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 AI rats at a dose of 6.6 $\mu$mole/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 AI rats at a constant rate (i.e., a bolus injection at a dose of 1.5 $\mu$mole/kg followed by a constant infusion at a rate of 1.5 $\mu$mole/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 AI.