RESUMEN
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.
Asunto(s)
Lesión Renal Aguda/metabolismo , Antibacterianos/farmacología , Antivirales/efectos adversos , Ganciclovir/efectos adversos , Levofloxacino , Ofloxacino/farmacología , Convulsiones/metabolismo , Lesión Renal Aguda/complicaciones , Animales , Antibacterianos/administración & dosificación , Antibacterianos/sangre , Antibacterianos/líquido cefalorraquídeo , Antivirales/sangre , Antivirales/líquido cefalorraquídeo , Relación Dosis-Respuesta a Droga , Ganciclovir/sangre , Ganciclovir/líquido cefalorraquídeo , Infusiones Intravenosas , Masculino , Ofloxacino/administración & dosificación , Ofloxacino/sangre , Ofloxacino/líquido cefalorraquídeo , Ratas , Ratas Wistar , Convulsiones/inducido químicamente , Convulsiones/complicacionesRESUMEN
BACKGROUND: Alterations of hepatic drug metabolism in patients with renal failure are poorly understood. In this study, the effects of uremic substances that can be removed by hemodialysis on in vitrohepatic drug metabolism were studied using human liver microsomes and hepatocytes. METHODS: The metabolism of various compounds that undergo oxidation and glucuronidation in the liver was studied using human liver microsomes and hepatocytes in the presence of 11 uremic substances removable by hemodialysis. RESULTS: The formation of resorufin from ethoxyresorufin was inhibited by 3-indoxylsulfate and 3-indoleacetic acid. The formation of 6beta-hydroxytestosterone from testosterone was inhibited only by 3-indoxylsulfate. These uremic substances reduced the maximum metabolic rate but not the affinity, suggesting that the inhibitory mechanism was noncompetitive. The inhibition of formation of resorufin and 6beta-hydroxytestosterone by 3-indoxylsulfate was also observed in human hepatocytes. The elimination of nicardipine in liver microsomes was decreased significantly in the presence of 3-indoxylsulfate and 3-indoleacetic acid. CONCLUSION: The hepatic metabolism of certain drugs may be inhibited directly by uremic substances such as 3-indoxylsulfate that accumulate in the plasma in patients with chronic renal failure.