title: Effects of Escherichia coli lipopolysaccharide on telithromycin pharmacokinetics in rats: inhibition of metabolism via CYP3A.
abstract: It has been reported that telithromycin is metabolized primarily via hepatic microsomal cytochrome P450 (CYP) 3A1/2 in rats and that the expression of hepatic and intestinal CYP3A decreases in rats pretreated with Escherichia coli lipopolysaccharide (ECLPS rats; an animal model of inflammation). Thus, it is possible that the area under the plasma concentration-time curve from 0 h to infinity (AUC 0-infinity) of intravenous and oral telithromycin is greater for ECLPS rats than for the controls. To assess this, the pharmacokinetic parameters of telithromycin were compared after intravenous and oral administration (50 mg/kg). After intravenous administration of telithromycin, the AUC 0-infinity was significantly greater (by 83.4%) in ECLPS rats due to a significantly lower nonrenal clearance (by 44.5%) than in the controls. This may have been due to a significantly decreased hepatic metabolism of telithromycin in ECLPS rats. After oral administration of telithromycin, the AUC 0-infinity in ECLPS rats was also significantly greater (by 140%) than in the controls and the increase was considerably greater than the 83.4% increase after intravenous administration. This could have been due to a decrease in intestinal metabolism in addition to a decreased hepatic metabolism of telithromycin in ECLPS rats.
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, San 56-1, Shinlim-Dong, Kwanak-Gu, Seoul 151-742, South Korea.
authors.forename: Joo H
authors.initials: JH
authors.lastname: Lee
authors.forename: Yu K
authors.initials: YK
authors.lastname: Cho
authors.forename: Young S
authors.initials: YS
authors.lastname: Jung
authors.forename: Young C
authors.initials: YC
authors.lastname: Kim
authors.forename: Myung G
authors.initials: MG
authors.lastname: Lee
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004926:Escherichia coli / Q000378:metabolism; D007422:Intestines / Q000201:enzymology; D048628:Ketolides / Q000493:pharmacokinetics*; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology*; D008099:Liver / Q000201:enzymology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000900:Anti-Bacterial Agents; D048628:Ketolides; D008070:Lipopolysaccharides; D008565:Membrane Proteins; C496509:Cyp3a13 protein, mouse; D051544:Cytochrome P-450 CYP3A; C106791:telithromycin