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Antimicrobial Agents and Chemotherapy, March 2008, p. 1046-1051, Vol. 52, No. 3
0066-4804/08/$08.00+0     doi:10.1128/AAC.01210-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Effects of Escherichia coli Lipopolysaccharide on Telithromycin Pharmacokinetics in Rats: Inhibition of Metabolism via CYP3A{triangledown}

Joo H. Lee, Yu K. Cho, Young S. Jung, Young C. Kim, and Myung G. Lee*

College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, San 56-1, Shinlim-Dong, Kwanak-Gu, Seoul 151-742, South Korea

Received 13 September 2007/ Returned for modification 20 November 2007/ Accepted 16 December 2007

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 (AUC0-{infty}) 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 AUC0-{infty} 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 AUC0-{infty} 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.

* Corresponding author. Mailing address: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, San 56-1, Shinlim-Dong, Kwanak-Gu, Seoul 151-742, South Korea. Phone: 82 2 8807855. Fax: 82 2 8898693. E-mail: leemg{at}snu.ac.kr

{triangledown} Published ahead of print on 26 December 2007.

Antimicrobial Agents and Chemotherapy, March 2008, p. 1046-1051, Vol. 52, No. 3
0066-4804/08/$08.00+0     doi:10.1128/AAC.01210-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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