In vivo electrochemical detection of chloramphenicol in rat cortex was investigated with microelectrodes after intravenous injection of chloramphenicol succinate (170 mg·kg-1). A classical pharmacokinetic study with high-performance liquid chromatography (HPLC) determination of chloramphenicol was performed. The two methods gave the same result when chloramphenicol and chloramphenicol succinate were added for the HPLC assay and compared with the voltametric assay. Clinical applications of this new method are suggested.
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...
The right cerebral hemisphere of the rat was perfused in situ by retrograde bolus infusion of some nitroimidazole drugs into the external carotid artery. The right jugular vein served to collect blood samples. Drugs were continuously measured in the right cortex by microvoltametric electrodes and in blood samples by high-performance liquid chromatography during a few minutes. Cerebrovascular permeability coefficients of six nitroimidazoles ranged from 0.8 · 10––4 to 3 · 10––6 cm · s––1 and were directly proportional to the octanol-water partition coefficient of the solute. Thus, microvoltametry is a new method to study cerebrovascular transfer in the rat of electroactive antibiotics.
Disposition of cefsulodin (125 mg · kg––1) was studied in rat frontal cortex after intravenous injection of a bolus by two methods. In vivo voltametry and high performance liquid chromatography of cefsulodin in brain extracts gave different concentration values. The ratio of concentrations determined by the two methods was similar to the ratio of the extravascular volume to total volume. Thus, these findings evidenced the distribution of cefsulodin in the extravascular fluid of the rat frontal cortex.
Lipophilicity of the injectable form of some antibiotics was measured with a micromethod. The antibiotic was dissolved in a small volume (1 ml) of phosphate buffer at a physiological pH (pH = 7.4) and was extracted by a small volume of octanol (1 ml). HPLC determinations of the antibiotic were performed in the two phases, log P ranged from +1.3 for chloramphenicol to -4.3 for ceftriaxone. A linear relationship was established for a few antibiotics between the log P values found in our experiments and the log permeability calculated from data in the literature for human and rat brain. This linear relationship enabled the brain concentrations of antibiotics to be predicted in man and rats.
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