Effect of a newly developed ketolide antibiotic, telithromycin, on metabolism of theophylline and expression of cytochrome P450 in rats.
The effects of a newly-developed ketolide antibiotic, telithromycin, on the metabolism of theophylline and the expression of hepatic cytochrome P450 (CYP) 1A2 and CYP3A2 were investigated in rats. Telithromycin at a high dose (100 mg/kg of body weight) was injected intraperitoneally once a day for 3 days. Twenty-four hours (day 4) after the final administration of telithromycin, theophylline (10 mg/kg) was administered intravenously. The presence of telithromycin significantly delayed the disappearance of theophylline from plasma. Parameters related to the pharmacokinetic interaction between theophylline and telithromycin were examined by noncompartmental methods. A significant decrease in the systemic clearance of theophylline was observed in the presence of telithromycin. Pretreatment with telithromycin significantly decreased the metabolic clearance of the major metabolites, 1-methyluric acid and 1,3-dimethyluric acid, with no change in the renal clearance of theophylline, suggesting that the decreased systemic clearance of theophylline by telithromycin is due to reduction of their metabolic clearance. Pretreatment with telithromycin significantly decreased the activity of 7-ethoxyresorufin O-deethylation and testosterone 6 beta-hydroxylation, suggesting that telithromycin decreases the activity of hepatic CYP1A2 and CYP3A2. Western blot analysis revealed that telithromycin significantly decreased the protein levels of CYP1A2 and CYP3A2 in the liver, which could explain the observed decreases in the systemic clearance of theophylline and metabolic clearance of 1-methyluric acid and 1,3-dimethyluric acid. The present study suggests that telithromycin at the dose used in this study alters the pharmacokinetics and metabolism of theophylline, due to reductions in the activity and expression of hepatic CYP1A2 and CYP3A2.
Nosaka
Hiroyuki
H
Department of Medical Technology, Nagoya University School of Health Sciences, Daikominami, Higashi-ku, Nagoya 461-8673, Japan.
Nadai
Masayuki
M
Kato
Miki
M
Yasui
Kazumasa
K
Yoshizumi
Hideo
H
Miyoshi
Mika
M
Zhao
Ying Lan
YL
Baba
Kenji
K
Takagi
Kenzo
K
Hasegawa
Takaaki
T
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D015153:Blotting, Western; D001993:Bronchodilator Agents / Q000493:pharmacokinetics*; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D048628:Ketolides / Q000494:pharmacology*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013806:Theophylline / Q000493:pharmacokinetics*
D000900:Anti-Bacterial Agents; D001993:Bronchodilator Agents; D048628:Ketolides; D008565:Membrane Proteins; D003577:Cytochrome P-450 Enzyme System; D013806:Theophylline; D001189:Aryl Hydrocarbon Hydroxylases; C465260:Cyp3a2 protein, rat; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; C106791:telithromycin