ABSTRACT
In order to assess the apparent diffusion coefficient of two nitrosoureas (carmustine and fotemustine) in the brain, a model of planar diffusion was used in the rat brain and in rat and human brain biopsies. Drugs were deposed on the brain surface at a constant concentration for 30 min. At the end of the diffusion time, the concentration gradient was determined with microelectrodes using voltammetry at 5 different depths in the extracellular space of the gray matter (0-304 microns). Voltammetry with microelectrodes measured quantitatively intact drug in the brain extracellular space (CV 4% for the 2 drugs) in the range studied. The same procedure was used for human and rat brain biopsies which were held in a small cup. The apparent diffusion coefficients in living animals were 0.49 x 10(-6) cm2.s-1 for carmustine and 0.23 x 10(-6) cm2.s-1 for fotemustine; in human biopsies, they were 0.84 x 10(-6) cm2.s-1 for carmustine and 0.37 x 10(-6) cm2.s-1 for fotemustine. Significant differences in the apparent diffusion coefficients of the drugs were accounted for by the fact that the intracellular penetration of fotemustine was better than that of carmustine.
Subject(s)
Antineoplastic Agents/pharmacokinetics , Brain/metabolism , Carmustine/pharmacokinetics , Nitrosourea Compounds/pharmacokinetics , Organophosphorus Compounds/pharmacokinetics , Adult , Aged , Animals , Diffusion , Female , Humans , Male , Microelectrodes , Middle Aged , Rats , Rats, Inbred StrainsABSTRACT
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.
Subject(s)
Anti-Bacterial Agents/pharmacokinetics , Animals , Anti-Bacterial Agents/analysis , Brain Chemistry/drug effects , Chemical Phenomena , Chemistry, Physical , Diffusion , Gels , Male , Microelectrodes , Models, Biological , Rats , Rats, Inbred Strains , TemperatureABSTRACT
Carmustine and fotemustine were perfused using a bolus retrograde infusion into the right external carotid artery of rats. The right jugular vein gave blood samples. Using a previously described method, nitrosoureas were continuously measured in rat brain by voltammetry and in blood samples by high-performance liquid chromatography for 15 min. Cerebrovascular permeability coefficients calculated in the first 2 min were 0.9.10(-4) cm.s-1 for carmustine and 0.5.10(-4) cm.s-1 for fotemustine. These high brain permeability coefficients were compared to literature values for carmustine and other nitrosoureas determined with a radioactive procedure.
