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Active transport restricts distribution of 3H-benzyipenicillin along cerebrospinal fluid
2347 I P.fr.273 I
Active transport restricts distribution of 3H-benzy|penic|Hin along cerebrosphml fluid Bulat, M., Vladi6, A. and Striki6, N.
Department of Pharmacology, Medical Faculty Universityof Zagreb, 41001 Zagreb, Yugoslavia Distribution of drugs and endogeneous metabolites in the cerebrospinal fluid (CSF) systeni is poorly understood. Since active transport removes some of these substances out off CSF the question arises does active transport in such a way restrict their distribution to various CSF compartments. Benzylpenicillin (BP) is actively transported out off CSF and therapeutically applied into CSF (Fishman, 1966). In our experiments in dogs we applied 3H-BP in the cistema magna and followed its distribution to cortical, lumbar and ventricular CSF in control dogs and in animals pretreated with probenecid which blocks active transport of 3H-BP. In short ether anesthesia 300 ul of CSF from cisterna magna was withdrawn and the same volume of saline containing 3H-BP was applied through the same needle o,er 10 sec. At 90 or 180 min after intracisternal application of 3H-BP animals were anesthetized with sodium thiopental (45 mg/kg, i.p.) and samples of CSF (about 80 ul) were taken from cisterna magna, cortical and lumbar subarachnoid space and from lateral ventricle for analysis. Probenecid (150 mg/kg, i.p.) was given 60 min before 3H-BP application. In control animals removal of 3H-BP from cisternal CSF was fast, its half-life being 30 ~ . When active transport of 3H-BP was blocked by probenecid the half-life of 3H-BP in the cisternal CSF i~!creased to 63 min. Distribution of 3H-BP to cortical lumbar and ventricular CSF of control animals was extremely ~ow and Similar at both 90 and 180 min. In animals pretreated with probenecid distribution of 3H-BP to cortical ]umbar and veptricular CSF was enhanced. Furthermore a much higher concentration of 3H-BP in these CSF compartments was reached at 180 than at 90 min in probenecid pretreated animals. These results indicate that the active transport of 3H-BP keeps its concentration low in a CSF compartment so that its distribution to other CSF compartments is limited. After blockade of active transport by wobenecid the removal of 3H-BP out off CSF is slowed down and its distribution to remote CSF compartments is increased. It appears that in a similar way active transport of cerebral metabolites out off CSF can keep their concentra~on~ different in various compartments of CSF since their distribution between various CSF comp~tments is limited. Namely, under these conditions the concentration of metabolites in cerebral parenchyma and its diftUsion into adjacent CSF compartment should be a decisive factor in maintenance of gradients of these metabolites between various CSF compartments (Bulat 1977, 1984). In conclusion, our experiments with 3H-BP raise the question should active transport be blocked in patients to improve distribution of some drugs along CSF system. Supported by U.S.-Yugoslav Joint Board (JFP No. 721) and SIZ for Scientific Activity of Croatia.
References Bulat, M., 197"7_Brain Re-~ 122. 388. Bulat, M., 1984, Clin. Neuropharmacol. 7 (suppl. 1), 153. Fishman, R.A., 1966, Arch. Neurol. 15, 113.
Active transport restricts distribution of 3H-benzy|penic|Hin along cerebrosphml fluid Bulat, M., Vladi6, A. and Striki6, N.
Department of Pharmacology, Medical Faculty Universityof Zagreb, 41001 Zagreb, Yugoslavia Distribution of drugs and endogeneous metabolites in the cerebrospinal fluid (CSF) systeni is poorly understood. Since active transport removes some of these substances out off CSF the question arises does active transport in such a way restrict their distribution to various CSF compartments. Benzylpenicillin (BP) is actively transported out off CSF and therapeutically applied into CSF (Fishman, 1966). In our experiments in dogs we applied 3H-BP in the cistema magna and followed its distribution to cortical, lumbar and ventricular CSF in control dogs and in animals pretreated with probenecid which blocks active transport of 3H-BP. In short ether anesthesia 300 ul of CSF from cisterna magna was withdrawn and the same volume of saline containing 3H-BP was applied through the same needle o,er 10 sec. At 90 or 180 min after intracisternal application of 3H-BP animals were anesthetized with sodium thiopental (45 mg/kg, i.p.) and samples of CSF (about 80 ul) were taken from cisterna magna, cortical and lumbar subarachnoid space and from lateral ventricle for analysis. Probenecid (150 mg/kg, i.p.) was given 60 min before 3H-BP application. In control animals removal of 3H-BP from cisternal CSF was fast, its half-life being 30 ~ . When active transport of 3H-BP was blocked by probenecid the half-life of 3H-BP in the cisternal CSF i~!creased to 63 min. Distribution of 3H-BP to cortical lumbar and ventricular CSF of control animals was extremely ~ow and Similar at both 90 and 180 min. In animals pretreated with probenecid distribution of 3H-BP to cortical ]umbar and veptricular CSF was enhanced. Furthermore a much higher concentration of 3H-BP in these CSF compartments was reached at 180 than at 90 min in probenecid pretreated animals. These results indicate that the active transport of 3H-BP keeps its concentration low in a CSF compartment so that its distribution to other CSF compartments is limited. After blockade of active transport by wobenecid the removal of 3H-BP out off CSF is slowed down and its distribution to remote CSF compartments is increased. It appears that in a similar way active transport of cerebral metabolites out off CSF can keep their concentra~on~ different in various compartments of CSF since their distribution between various CSF comp~tments is limited. Namely, under these conditions the concentration of metabolites in cerebral parenchyma and its diftUsion into adjacent CSF compartment should be a decisive factor in maintenance of gradients of these metabolites between various CSF compartments (Bulat 1977, 1984). In conclusion, our experiments with 3H-BP raise the question should active transport be blocked in patients to improve distribution of some drugs along CSF system. Supported by U.S.-Yugoslav Joint Board (JFP No. 721) and SIZ for Scientific Activity of Croatia.
References Bulat, M., 197"7_Brain Re-~ 122. 388. Bulat, M., 1984, Clin. Neuropharmacol. 7 (suppl. 1), 153. Fishman, R.A., 1966, Arch. Neurol. 15, 113.