Effect of Experimental Renal Failure on the Pharmacodynamics of Cefoselis-Induced Seizures in Rats.

Abstract

Cefoselis (CFSL), a fourth-generation parenteral cephalosporin, has been marketed in Japan since September 1998. In December 1998, warnings of central nervous system (CNS) adverse effects such as seizures and confusional states were added to the labeling of CFSL. In many cases, these adverse effects were observed in patients who were elderly and/or had renal failure. Therefore renal failure is considered as one of the risk factors for neurotoxicity of CFSL. Since CFSL is mainly eliminated by renal excretion, 1) renal failure would be associated with increased serum concentrations of CFSL. On the other hand, it is still unknown whether renal failure can alter the pharmacodynamics of CFSL-induced seizures.Drug administration can be divided into two phases: a pharmacokinetic phase in which dose, dosage form, frequency, and route of administration are related to drug concentration-time relationships in the body; and a pharmacodynamic phase in which the concentration of drug at the site(s) of action is related to the magnitudes of the effect(s) produced.2) The pathophysiologic status of patients can affect both the pharmacokinetics and the pharmacodynamics of a drug. Our knowledge of the effects of disease on the pharmacokinetics of a drug cannot be used to optimize the drug dosage of a patient without information on disease effects on the pharmacodynamics. 3) Therefore it is important to distinguish the effects of disease on the pharmacokinetics from those on the pharmacodynamics. Danhof and Levy 3) reported an experimental strategy to assess the effects of disease and other variables on the pharmacodynamics of drugs with CNS activity. The effects of experimental renal failure on the pharmacodynamics of CNS stimulant drugs such as theophylline, 4) pentylentetrazole, 5) and cimetidine 6) were investigated previously.There have been clinical case reports of seizures caused by various b-lactam antibiotics such as penicillin, 7) cefazoline, 8) ampicillin, 9) and imipenem. 10) However, to our knowledge, there have been no reports that clarified the effect of renal failure on the pharmacodynamics of b-lactam antibiotic-induced seizures. To assure safe and effective antibiotic drug therapy, it must be determined if renal failure can change the relationship between the concentration and intensity of pharmacologic activity of drugs.The present study was designed to determine: 1) the suitability of the rat as an animal model of CFSL-induced seizures; 2) the sampling site where CFSL concentrations reflect the drug concentration at the site of neurotoxic action; and 3) the effect of renal failure on the pharmacodynamics of CFSL-induced seizures. MATERIALS AND METHODS AnimalsMale Wistar rats weighing 240 to 300 g were used in this investigation. The rats had an indwelling cannula implanted in the left juglar vein under light ether anesthesia one day before the experiment and they were fasted until the CFSL infusion began.Chemicals CFSL sulfate (Wincef ® for infusion) used for animal experiments was obtained from Fujisawa Pharmac...

Altered electrolyte handling of the choroid plexus in rats with glycerol‐induced acute renal failure

“…A similar observation has been reported for fluoroquinolones, in which their brain concentrations at the onset of their seizure induction decrease as the renal function decreases [2,3]. As for the precise mechanism accounting for the altered sensitivity, it is not fully understood at present, but various studies have been performed to date [4][5][6], and some of them have suggested that the perturbed neural function and/or modified neural signal handling are largely responsible for the alteration, in which a difference in the potencies of the neuromuscular blockers was reported and an increased sympathetic activity in patients with an impaired renal function was demonstrated [7][8][9].…”

Decreased Lithium Disposition to Cerebrospinal Fluid in Rats with Glycerol-induced Acute Renal Failure

“…This increased CNS sensitivity is possibly related to a perturbation in electrolyte homeostasis in the CNS (17). In fact, there are some reports indicating that changes in the sodium concentration of cerebrospinal fluid (CSF) affect the expression of receptors like the angiotensin type 1A receptor, and this consequently influences various enzyme activities and/or the autonomic nervous system (18,19).…”

Mechanisms of antibiotic neurotoxicity in renal failure

“…Increased brain permeability for radiolabelled inulin and sucrose, for instance, had been demonstrated formerly in uremic rats [13]. Such permeability change or generalised dysfunction of the blood-brain barrier was reaffirmed by the observations of increased protein concentration in the cerebrospinal fluid after renal failure [14] and increased cerebrospinal fluid/serum bromide concentration ratio in uraemic humans, in whom the abnormality was reversible after recovery of renal function [15].…”

“…Simply taking into account drug distribution in blood and/or cerebrospinal fluid compartments would be of little use for risk estimation. Besides, the convulsive threshold after antibiotic administration in the renal failure population is confounded by the presence of endogenous uraemic toxins such as potentially neurotoxic guanidino compounds [14,23]. Conceivably, these factors account for the difficulty in prediction of central nervous system antibiotic neurotoxicity in clinical practice [24].…”