Alteration of fexofenadine disposition in the rat isolated perfused liver following injection of bacterial lipopolysaccharide.
1. The aim of the present study was to examine the effect of bacterial lipopolysaccharide (LPS) on the disposition of an organic anion transporting polypeptide and P-glycoprotein substrate in the rat isolated perfused liver. 2. Male Sprague-Dawley rats were divided into four groups. Three of the groups received 1, 2.5 or 5 mg/kg, i.p., Escherichia coli LPS in sterile saline. The fourth group received an equivalent volume of sterile saline i.p. Twenty-four hours after treatment, rats were anaesthetized and the liver isolated and perfused with fexofenadine at an initial concentration of 2000 ng/mL in a recirculating system. Perfusate and bile samples were collected for 60 min and the liver was collected at the end of the perfusion. Fexofenadine concentrations were determined by HPLC. Fexofenadine pharmacokinetic parameters, the final liver : perfusate (L : P) and bile : liver (B : L) concentration ratios were determined. 3. Injection of LPS changed the hepatic disposition of fexofenadine. The changes were most marked in the 5 mg/kg LPS group. Notably, clearance from the perfusate (CL) and into the bile (CLB; 5.9 +/- 0.6 and 1.24 +/- 0.20 mL/min, respectively), L : P (44 +/- 11) and B : L (17 +/- 2) were all reduced (P < 0.05) in this group compared with control (CL 10.0 +/- 1.1 mL/min; CLB 2.7 +/- 0.5 mL/min; L : P 87 +/- 14; and B : L 30 +/- 4). 4. In conclusion CL and CLB were reduced following treatment with LPS in a manner consistent with downregulation of both canalicular and sinusoidal transport.
Tong
Yen
Y
Sansom Institute, School of Pharmacy and Medical Sciences, University of South Australia, City East Campus, Adelaide, South Australia, Australia.
Zhang
Ruhong
R
Ngo
Suong N T
SN
Davey
Andrew K
AK
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D001646:Bile / Q000378:metabolism; D001659:Biliary Tract / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006634:Histamine H1 Antagonists / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D007700:Kinetics; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D027361:Organic Anion Transporters / Q000378:metabolism; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D016593:Terfenadine / Q000031:analogs & derivatives* / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D006634:Histamine H1 Antagonists; D008070:Lipopolysaccharides; D027361:Organic Anion Transporters; D016593:Terfenadine; C093230:fexofenadine