Effects of acute renal failure and ganciclovir on the pharmacodynamics of levofloxacin-induced seizures in rats.

Seizures have been reported in patients receiving fluoroquinolones, including levofloxacin (LVFX). In the present study, we investigated the effects of experimental renal failure and the concomitant treatment with ganciclovir on the pharmacodynamics of LVFX-induced seizures to identify whether these factors can alter the pharmacokinetics or the pharmacodynamics of LVFX. Male Wistar rats received an intravenous infusion of LVFX at 250, 500, or 1000 mg/h/rat until the onset of seizures, and samples of serum, brain, and cerebrospinal fluid (CSF) were obtained. The concentration of LVFX in CSF at the onset of seizures was not affected by the infusion rate, whereas that in serum and brain increased with increasing infusion rate. This suggests that the concentration of LVFX in CSF is an appropriate index of the drug concentration at the site of action. The concentration of LVFX in CSF at the onset of seizures was significantly lower in rats with renal failure than in the control rats. Pretreatment with methylguanidine, an uremic toxin, at 600 mg/h/rat for 8 min reduced the concentration of LVFX in CSF at the onset of seizures and the total body clearance of LVFX after the intravenous injection. In rats pretreated with ganciclovir at 500 mg/h/rat for 1 h, the concentration of LVFX in CSF at the onset of seizures was significantly lower than the control rats. These results suggest that renal failure and ganciclovir can be the risk factors for LVFX-induced seizures, and that they increase the sensitivity of the central nervous system to LVFX-induced seizures.

Effect of levofloxacin on serum glucose concentration in rats.

To clarify the mechanism of fluoroquinolone-induced abnormalities in blood glucose, the effect of levofloxacin on serum glucose concentration was investigated in rats. Rats received an intravenous injection of levofloxacin and their arterial blood was sampled periodically. The serum glucose concentration decreased after an injection of 100 mg/kg of levofloxacin, while it increased at levofloxacin 300 mg/kg. The serum immunoreactive insulin concentration increased as the dose of levofloxacin increased. The serum epinephrine concentration was rapidly elevated by levofloxacin at 300 mg/kg. The serum histamine concentration increased after injections of levofloxacin, 200 and 300 mg/kg. Diphenhydramine (1 mg/kg) antagonized the hyperglycemia induced by 300 mg/kg of levofloxacin. In an in vitro study, the release of epinephrine from the adrenal medulla in the presence of levofloxacin was determined. Levofloxacin (300 microg/ml) did not affect epinephrine release from the adrenal medulla. Levofloxacin can induce hypoglycemia and hyperglycemia in rats. Levofloxacin can promote histamine release, leading to an increased serum epinephrine concentration and hyperglycemia.