Cimetidine Elimination from the Cerebrospinal Fluid of the Rat

The major goal of this study was to develop a small animal model that could be used to assess quantitatively the clearance of cimetidine from the cerebrospinal fluid (CSF) under relatively physiologic conditions. In addition, we addressed questions related to the pathways involved in the elimination of cimetidine from the CSF. We administered high and low bolus doses of cimetidine together with inulin, as a marker of bulk flow, into the lateral ventricle of anesthetized rats and sampled CSF from the cisterna magna. Principles of linear pharmacokinetic systems were applied to the data to obtain clearances from the CSF. The clearance of inulin was 2.02 ± 0.22 µl/min, which is in excellent agreement with the CSF production rate of 2.2 µl/min in anesthetized rats. The clearance of cimetidine from the CSF following the administration of a low dose was 11.8 ± 3.1 µl/min, which is in good agreement with the cimetidine CSF clearance in the rat obtained previously in studies using the technique of ventriculocisternal perfusion. A 32% decrease in the CSF clearance of cimetidine (P < 0.05) was observed when the high dose was administered, suggesting that CSF elimination is saturable. The clearance of inulin was unaffected by the high dose of cimetidine. This study demonstrates that the technique of lateral ventricle injection and sampling from the cisterna magna is useful in quantitatively assessing the elimination of compounds from the CSF in the rat under relatively physiologic conditions.     

Cimetidine transport in isolated brush border membrane vesicles from bovine choroid plexus

The purpose of this study was to elucidate the mechanisms involved in the transport of cimetidine across the brush border membrane of choroid plexus epithelium. Brush border membrane vesicles were prepared from bovine choroid plexus and the uptake of [3H]cimetidine was studied using the methods of rapid vacuum filtration and scintillation counting. Cimetidine accumulated in the vesicles with time reaching equilibrium within 2 hr. The amount of cimetidine taken up by the vesicles at equilibrium decreased with increasing extravesicular media osmolarity suggesting that cimetidine accumulates in an osmotically reactive intravesicular space. Binding of cimetidine to the membrane was estimated to be less than 18%. Michaelis-Menten studies demonstrated that cimetidine transport involved both a saturable and a nonsaturable component. The Vmax and Km (mean +/- S.E.) were 16.7 +/- 5.9 pmol/sec/mg protein and 58.1 +/- 3.1 microM, respectively, suggesting that cimetidine is transported across the choroid plexus brush border membrane with a lower affinity and a higher capacity than across the renal brush border membrane. The organic cation, quinidine (0.1 mM), and the amino acid, histidine (20 mM), both significantly reduced the initial, but not the equilibrium, uptake of cimetidine. However, high concentrations (5 mM) of more polar organic cations including tetraethylammonium, as well as of several organic anions including salicylate did not inhibit cimetidine transport. Studies with unlabeled cimetidine revealed a countertransport phenomenon. Attempts to drive the concentrative uptake of cimetidine with various ion gradients were unsuccessful. Of note was the fact that an outwardly directed proton gradient could significantly accelerate the uptake of cimetidine.(ABSTRACT TRUNCATED AT 250 WORDS)