Effect of Bile Duct Ligation and Unilateral Nephrectomy on Brain Concentration and Convulsant Potential of the Quinolone Antibacterial Agent Levofloxacin in Rats

To mimic the excretion route of the quinolone antibacterialagent levofloxacin (LVFX) in humans, we produced an excretion-limited(EL) model in male Sprague–Dawley rats by bile duct ligationand unilateral nephrectomy. We then examined the relationshipbetween brain levels of LVFX and its convulsant effects in controland EL animals. Serum concentrations of LVFX in EL animals (EL+ LVFX) were 2.38- and 1.59-fold and brain concentrations were1.33- and 1.19-fold those of the controls (control + LVFX) at30 min after a single intravenous injection of 10 and 100 mg/kgLVFX, respectively. Furthermore EL animals became more susceptibleto the convulsant effect of LVFX with a 1.28-fold decrease inconvulsion-inducing dose. In combination with oral pretreatmentwith 400 mg/kg 4-biphenylacetic acid (BPAA), convulsion-inducingdoses in the control (control + LVFX + BPAA) and EL (EL + LVFX+ BPAA) groups were markedly decreased by 2.25 and 9 times thatof the control + LVFX group. EL operation and BPAA pretreatmentslowed the elimination of LVFX in the serum and brain 4 hr laterin the following order: EL + LVFX + BPAA, control + LVFX + BPAA,EL + LVFX, and control + LVFX groups. This order reflects thatfor the convulsion-inducing doses. These results suggest thatEL rats may be a useful model for humans and that the convulsanteffect of LVFX with or without BPAA arises not only from theattainment of maximum brain concentration but also from delayeddisappearance from the brain.