Pharmacokinetic-Pharmacodynamic Modeling of the Electroencephalogram Effect of Imipenem in Healthy Rats

Self Cite

The aim of this study was to investigate the influence of hypovolemia on the distribution of imipenem in muscle extracellular fluid determined by microdialysis in awake rats. Microdialysis probes were inserted into the jugular vein and hind leg muscle. Imipenem recoveries in muscle and blood were determined in each rat by retrodialysis by drug before drug administration. Hypovolemia was induced by removing 40% of the initial blood volume over 30 min. Imipenem was infused intravenously at a dose of 70 mg · kg ؊1 over 30 min, and microdialysis samples were collected for 120 min from hypovolemic (n ‫؍‬ 8) and control (n ‫؍‬ 8) rats. The decay of the free concentrations in blood and muscle with time were monoexponential, and the concentration profiles in muscle and blood were virtually superimposed in both groups. Accordingly, the ratios of the area under the concentration-time curve (AUC) for tissue (muscle) to the AUC for blood were always virtually equal to 1. Hypovolemia induced a 23% decrease in the clearance (P < 0.05) of imipenem, with no statistically significant alteration of its volume of distribution. This study showed that imipenem elimination was altered in hypovolemic rats, probably due to decreased renal blood flow, but its distribution characteristics were not. In particular, free imipenem concentrations in blood and muscle were always virtually identical.Nosocomial infections are of primary concern in critical care departments; and because hospitalized patients suffer from major physiological alterations with potential consequences on drug pharmacokinetics, selection of the appropriate antibiotic dosing regimens appears to be very challenging (28). Because infections occur in tissues, measurement of free antibiotic concentrations in the interstitial fluid of tissues should be the most relevant for prediction of therapeutic efficacy, at least for extracellular pathogens. Microdialysis is an elegant technique that allows such determinations (6) and that has been used to demonstrate that the tissue distributions of several antibiotics, including piperacillin (2, 15), cefpirome (16), meropenem (32), and imipenem (IPM) (31), were impaired in critical care patients. However, not only the disease state itself but also iatrogenic procedures, such as surgery or intensive care treatment, might influence drug kinetics (2, 17); and therefore, the reasons for the altered distribution are not clear. Yet, it was hypothesized that reduced tissue perfusion contributes to the reduced IPM distribution (31).Experiments with animals allow better control of these multiple interfering parameters, and many microdialysis studies have also been conducted with rats to investigate the distribution of amino ␤-lactams in muscle (4,7,18,20,21,22,24,25). Muscle tissue has frequently been chosen because it is relatively accessible and the concentrations in muscle tissue seem to be a reasonable predictor of the unbound concentrations in more therapeutically relevant tissues, such as lung tissue (7,20,21). A microdialysis study condu...

Section: Methodsmentioning

confidence: 99%

Lack of Effect of Experimental Hypovolemia on Imipenem Muscle Distribution in Rats Assessed by Microdialysis

Marchand

Dahyot

Lamarche

et al. 2005

Self Cite

“…We have recently developed an experimental approach using quantitative electroencephalogram (EEG) recording together with pharmacokinetic-pharmacodynamic (PK-PD) modeling to characterize the epileptogenic activity of imipenem in rats (9). This investigation led to the conclusion that there was no simple direct relationship between the antibiotic's concentration in plasma and its EEG effect.…”

mentioning

confidence: 99%

Pharmacokinetic-Pharmacodynamic Modeling of the Electroencephalogram Effect of Norfloxacin in Rats

Chenel¹,

Barbot

Dupuis

et al. 2003

Self Cite

A previously developed pharmacokinetic-pharmacodynamic (PK-PD) modeling approach was used to investigate the epileptogenic activity of norfloxacin as a representative antibiotic with concentration-dependent antimicrobial activity. Rats received an intravenous infusion of norfloxacin at a rate of 5 mg kg of body weight ؊1 min ؊1 over 30 min. Blood samples were collected for drug assay, and an electroencephalogram (EEG) was recorded during infusion and postinfusion. An important delay was observed between concentrations of norfloxacin in plasma and the EEG effect. Indirect effect models failed to describe these data, which were successfully fitted by using an effect compartment model with a spline function to describe the relationship between effect and concentration at the effect site, as previously observed with imipenem. The robustness of the PK-PD model was then assessed by keeping the dose constant but increasing the duration of infusion to 120 and 240 min. Although this was accompanied by PK modifications, PD parameters did not vary significantly, and the PK-PD model still applied. In conclusion, the successful PK-PD modeling of the norfloxacin EEG effect in rats should be considered to predict and reduce the epileptogenic risk associated with this antibiotic as a representative fluoroquinolone (E. Fuseau and L. B. Sheiner, Clin. Pharmacol. Ther. 35:733-741, 1984).Some anti-infectious compounds, including fluoroquinolones and carbapenem antibiotics, may induce central nervous system (CNS) side effects that vary in both intensity and frequency (3, 18). We have recently developed an experimental approach using quantitative electroencephalogram (EEG) recording together with pharmacokinetic-pharmacodynamic (PK-PD) modeling to characterize the epileptogenic activity of imipenem in rats (9). This investigation led to the conclusion that there was no simple direct relationship between the antibiotic's concentration in plasma and its EEG effect. However, for the same dose administered, the intensity of this undesirable effect could be dramatically reduced by decreasing the infusion rate and thereby increasing its duration. Dose fractionation should therefore limit the epileptogenic risk. Fluoroquinolones belong to another category of antibiotics with potential convulsant risk (3, 18). Our group has extensively investigated the convulsant activity of norfloxacin (NOR) by crude PK-PD approaches in laboratory animals (6-8). The purpose of the present work is to characterize NOR's epileptogenic activity as a representative fluoroquinolone by quantitative EEG recording and PK-PD modeling in rats. MATERIALS AND METHODS Chemicals. NOR was obtained from Sigma (Saint-Quentin Fallavier, France).A NOR salt was prepared as previously described (7). All chemicals used were of analytical grade, and analytical solvents were of high-performance liquid chromatography grade.Animals. Male Sprague-Dawley rats from Depres Breeding Laboratories (St. Doulchard, France), weighing 292 Ϯ 34 g, were used. The animals were placed in wire cages...

“…However, the present study was conducted with Sprague-Dawley rats receiving norfloxacin at 150 mg/kg of body weight compared to Wistar rats treated with 300 mg/kg of norfloxacin in the previous experiment (10), which could partially explain this apparent discrepancy. The difficulty of finding doses appropriate for the inducement of reversible and therefore nonlethal seizures but sufficiently severe to have an effect on the EEG signal was previously mentioned (2,5). Preliminary tests suggested that a 300 mg/kg dose of norfloxacin was too high for the present study, and the 150 mg/kg dose was considered a better compromise.…”

mentioning

confidence: 93%

“…The goodness of fit of each model was assessed by visual inspection and analysis of the residuals and of the percentage of the coefficient of variation associated to parameter estimates (2,5). Two control animals underwent the same experimental protocol except that norfloxacin administration was replaced by isotonic saline administration.…”

mentioning

confidence: 99%

“…In rats treated with imipenem (5) and norfloxacin (2), increases in the total power of the EEG signal are related to behavioral modifications and the occurrence of tremor and partial seizures and can therefore be considered an appropriate surrogate pharmacodynamic (PD) end point for the investigation of the convulsant activity of these antibiotics in rats. Furthermore, the kinetics of this effect can be very precisely evaluated using pharmacokinetic (PK)-PD modeling techniques (2,5).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Norfloxacin-Induced Electroencephalogram Alteration and Seizures in Rats Are Not Triggered by Enhanced Levels of Intracerebral Glutamate

Chenel¹,

Limosin²,

Marchand³

et al. 2003

Self Cite

Pharmacokinetic-pharmacodynamic modeling of the electroencephalogram (EEG) effect was combined with intracerebral glutamate determinations using microdialysis for rats receiving norfloxacin intravenously (150 mg/kg of body weight). The EEG effect (accompanied by tremors and seizures) was consistently observed without glutamate level modifications. Therefore, norfloxacin-inducted seizures are not triggered by intracerebral glutamate level enhancement.Fluoroquinolone antibiotics may induce central nervous system excitatory side effects, including anxiety, nervousness, hallucination, and even seizures on rare occasions (3, 13). It is usually asserted that these excitatory side effects result from inhibition of GABA (␥-aminobutyric acid) binding to its receptors (1, 11). Using intracerebral microdialysis, however, Smolders et al. have previously observed in conscious rats norfloxacin-induced convulsions accompanied not by any apparent effect on the extracellular hippocampal GABA levels but rather by enhanced intracerebral glutamate concentrations (10). Studies of the relationship between glutamate concentrations and epileptic seizures have yielded conflicting observations, as recently reviewed (12). Smolders et al. have hypothesized that enhanced glutamate levels might be essential for the induction of norfloxacin seizures (10), but it could also be argued that the generation, spreading, and maintenance of seizures eventually leads to glutamate release and elevation (9). Quantitative electroencephalogram (EEG) recording combined with intracerebral microdialysis offers a unique opportunity to address this question. In rats treated with imipenem (5) and norfloxacin (2), increases in the total power of the EEG signal are related to behavioral modifications and the occurrence of tremor and partial seizures and can therefore be considered an appropriate surrogate pharmacodynamic (PD) end point for the investigation of the convulsant activity of these antibiotics in rats. Furthermore, the kinetics of this effect can be very precisely evaluated using pharmacokinetic (PK)-PD modeling techniques (2, 5).The objective of this study was therefore to combine quantitative EEG recording (for the characterization of seizure induction and maintenance) with intracerebral microdialysis using the hippocampus (for the measurement of glutamate levels) of rats (after the administration of norfloxacin) to look for a causality relationship between the two factors. The experiment was conducted in accordance with the Principles of Laboratory Animal Care (National Institutes of Health), and ethical approval was obtained from the Animal Ethics Committee of the Faculty of Pharmacy (BHE 2001/12/ AE). Norfloxacin was obtained from Sigma (Saint-Quentin Fallavier, France), and a salt was prepared as previously described (4). L-glutamate standards were supplied by Sigma. All chemicals used were of analytical grade, and the analytical solvents used were of high-performance liquid chromatography grade. Six male Sprague-Dawley rats (weighing 299 Ϯ 15 g)...