Telithromycin pharmacokinetics in rat model of diabetes mellitus induced by alloxan or streptozotocin.
OBJECTIVE
It has been reported that telithromycin is primarily metabolized via hepatic CYP3A1/2 in rats, the expression and/or mRNA level of hepatic CYP3A1/2 increase in rat model of diabetes mellitus induced by alloxan (DMIA) or streptozotocin (DMIS), and intestinal CYP3A1/2 enzyme activity decreases in rat model of DMIS. Thus, the pharmacokinetic changes of telithromycin in both models of diabetes mellitus compared with those in the control rats were evaluated.


METHODS
Telithromycin was administered (50 mg/kg) intravenously or orally to both rat models of diabetes and their respective control rats.


RESULTS
After intravenous administration of telithromycin to both models of diabetes, the non-renal clearance (CLNR) was significantly faster (32.3 and 53.1% increase for rat models of DMIA and DMIS, respectively) and the AUC was significantly smaller (25.0 and 33.8% decrease, respectively) than those in their respective controls. However, after oral administration of telithromycin, the AUC was comparable to that in their respective controls.


CONCLUSIONS
The faster CLNR after intravenous administration was due to increased hepatic CYP3A1/2 in both models of diabetes. The comparable AUC after oral administration was mainly due to decreased intestinal CYP3A1/2 activity. Alloxan and streptozotocin appear to influence some pharmacokinetics of telithromycin in a different fashion.
Lee
Joo H
JH
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, San 56-1, Shinlim-Dong, Kwanak-Gu, Seoul, 151-742, South Korea.
Lee
Myung G
MG
D000496:Alloxan; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000903:Antibiotics, Antineoplastic; D019540:Area Under Curve; D001798:Blood Proteins / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced* / Q000378:metabolism*; D003956:Dialysis; D007275:Injections, Intravenous; D007413:Intestinal Mucosa / Q000378:metabolism; D048628:Ketolides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008099:Liver / Q000378:metabolism; D008297:Male; D008861:Microsomes / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin
D000900:Anti-Bacterial Agents; D000903:Antibiotics, Antineoplastic; D001798:Blood Proteins; D048628:Ketolides; D013311:Streptozocin; D000496:Alloxan; C106791:telithromycin