Time-dependent effects of Klebsiella pneumoniae endotoxin on the telithromycin pharmacokinetics in rats; restoration of the parameters in 96-hour KPLPS rats to the control levels.

OBJECTIVES

It has been reported that telithromycin is primarily metabolized via hepatic CYP3A4 and 3A1/2 in humans and rats, respectively, and that the protein expression of hepatic CYP3A subfamily significantly decreased (59.1% decrease) in 24-h KPLPS rats (lipopolysaccharide derived from Klebsiella pneumoniae; the protein expression was measured 24h after KPLPS administration) compared with that in control rats, but restored to that in control rats in 96-h KPLPS rats.

METHODS

The pharmacokinetic parameters of telithromycin were compared after intravenous and oral administration at a dose of 50mg/kg to control, 24-h KPLPS, and 96-h KPLPS rats.

RESULTS

After both intravenous and oral administration of telithromycin to 24-h KPLPS rats, the AUC of telithromycin became significantly greater (68.2% and 88.7% increase for intravenous and oral administration, respectively) and this could have been due to the significantly slower CL(NR) (45.7% decrease). Because telithromycin is a low hepatic extraction ratio drug, the slower CL(NR) could have been due to the decreased protein expression of the hepatic CYP3A subfamily compared with that in control rats, and was supported by the significantly slower in vitro CL(int) in hepatic microsomes (13.1% decrease). However, in 96-h KPLPS rats, the pharmacokinetic parameters of telithromycin restored fully to those in control rats due to restoration of the protein expression of the hepatic CYP3A subfamily to that in control rats. The protein expression of the intestinal CYP3A subfamily was comparable among three groups of rats.

CONCLUSIONS

These findings indicate the existence of the time-dependent effects of KPLPS on the pharmacokinetics of telithromycin in rats.