On-Line Pharmacokinetics of Chloramphenicol in Rat Cortex by in vivo Electrochemical Detection

A method for determining diffusion coefficients of four antibiotics in extracellular tissue space according to Fick's law is described. This new method was applied to rat brain tissue and to agar. After diffusion of the antibiotic in one axis, the gradient concentration was determined with microvoltammetric electrodes. These microelectrodes (1 micron at the extreme tip) measured the free diffusible form of electroactive antibiotics in the extracellular brain space. Metronidazole, chloramphenicol succinate, cefsulodin, and piperacillin gave diffusion coefficients ranging from 0.1 x 10(-6) to 0.2 x 10(-6) cm2 . s-1 in tissue; chloramphenicol base, which is positively charged, gave a coefficient of 0.04 x 10(-6) cm2 . s-1. The coefficient ranged from 0.6 x 10(-6) to 1.2 x 10(-6) cm2 . s-1 in agar. These coefficients were used to simulate antibiotic concentrations in infectious sites and between capillaries by using a simple model of plane diffusion.

Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Measurement and clinical and pharmacokinetic implications of diffusion coefficients of antibiotics in tissues

Meulemans

Paycha

Hannoun

et al. 1989

“…Concentrations of chloramphenicol and piperacillin in plasma and CSF samples were measured by high-pressure liquid chromatography with micromethods (8,10). Standard dilutions of both drugs were prepared with drug-free rat plasma and artificial CSF and stored at -80°C with unknown samples.…”

Section: Methodsmentioning

confidence: 99%

Continuous sampling for determination of pharmacokinetics in rat cerebrospinal fluid

Meulemans¹,

Vicart²,

Mohler³

et al. 1986

A method for determining drug concentration relationships between plasma and cerebrospinal fluid (CSF) in rats is described. Continuous CSF samples were collected directly from the third anterior ventricle with an indwelling cannula inserted through the bregma point, and drug concentrations were determined by high-pressure liquid chromatography and radioimmunoassay iicromethods. Three antibiotics with different abilities to cross the blood-CSF barrier (chloramphenicol, piperacillin, and gentamicin) were tested. This method was found to be reproducible for each drug even if the antibiotic levels were low and the sample volumes very small. Peak CSF concentrations occurred between 0.75 and 1.25 h after injection for all three antibiotics. Percent penetration values at 1 h were 50, L2, and 5.4% for chloramphenicol, piperacillin, and gentamicin, respectively. Several techniques have been described for collecting cerebrospinal fluid (CSF) from various animals (13). In larger animals such as rabbits and dogs, continuous sampling of CSF in pharmacokinetic studies is done with a cannula implanted generally in the cisterna magna. The present report presents a simple, rapid cannulation technique for repeated sampling of CSF in rats. The CSF samples were collected directly from the third anterior ventricle with an indwelling cannula.This technique was tested and applied to study the pharmacokinetics in the CSF of three antibiotics from different families (chloramphenicol, piperacillin, and gentamicin) chosen for their varying ability to cross the blood-CSF barrier in mammalian species (2-4, 6). MATERIALS AND METHODSAnimals. Male Wistar rats (350 g) were anesthetized by intraperitoneal injection of urethane (1.25 g kg-1), and a catheter was inserted in the aortic arch by the carotid artery to allow blood sampling and antibiotic injection. The animals werte then placed on a stereotaxic table or in a surgical head holder. During deep anesthesia a subcutaneous injection of 2% Xylocaine was given locally. Five minutes later a hole was made in the skull at the bregma point (Fig. 1), and a cannula (1-mm external diameter) with a mandrel was placed into the third ventricle 6.5 mm under the brain surface. The mandrel was removed, and a needle (0.5-mm external diameter) was inserted into the cannula. This needle connected with polyethylene tubing to a peristaltic pump (Gilson) (flow rate, 2 ml min 1). Under these conditions, the CSF flow rate was 1 ,ul min 1 and was stable throughout the course of the experiment, which lasted 3 h. CSF was sampled every 15 min in small conical polypropylene tube (Ependorff). Arterial blood pressure was controlled and remained stable during the experiment.Monosuccinate sodium chloramphenicol (165 mg kg-1), piperacillin sodium (20 mg kg '), and gentamicin sulfate (20 mg kg-1) were injected in a bolus in the arterial catheter. * Corresponding author.High-pressure liquid chromatography assay. Concentrations of chloramphenicol and piperacillin in plasma and CSF samples were measured by high-pressure liquid...

“…This technique, called voltammetry, has been described many times (8,11). Briefly, a microelectrode of 1-,um diameter detects electroactive antibiotic concentrations without delay.…”

mentioning

confidence: 99%

A model of cefoperazone tissue penetration: diffusion coefficient and protein binding

Meulemans

1992

The apparent diffusion coefficient of a bound drug, cefoperazone, was studied. The protein binding of cefoperazone was studied by voltammetry, a technique which permitted instant measurements. The apparent diffusion coefficients were similar in agar and fibrin and lower in rat brain tissue. The influence of protein on the value of the apparent diffusion coefficient was negligible. The hypothesis that only the free drug diffuses was supported. The percentage of binding determined by voltammetry corresponded to the true concentration of drug which diffuses and is much lower than the percentage of binding determined by the ultrafiltration centrifugation method. This discrepancy could be explained by the rate of dissociation of the protein-drug complex.