Abstract
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.
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REFERENCES
A. Somogyi and R. Gugler, Clin. Pharmacokinet. 8:463–495 (1983).
J. J. Schentag, F. B. Cerra, G. M. Calleri, M. E. Leising, M. A. French, and H. Bernhard. Clin. Pharmacol. Ther. 29:737–743 (1981).
J. J. Schentag, F. B. Cerra, G. Calleri, J. Q. Rose, E. De Glopper, and H. Bernhard. Lancet 1:177–181 (1979).
B. S. Kimelbatt, F. B. Cerra, G. Calleri, M. J. Berg, M. A. McMillen, and J. J. Schentag. Gastroenterology 78:791–795 (1980).
H. F. Cserr. Physiol. Rev. 51:273–311 (1971).
K.-A. Jonsson, S.-E. Eriksson, I. Kagevi, B. Norlander, G. Bodemar, and A. Walan. Br. J. Clin. Pharmacol. 14:815–819 (1982).
K.-A. Jonsson, S.-E. Eriksson, I. Kagevi, B. Norlander, G. Bodemar, and A. Walan. Br. J. Clin. Pharmacol. 17:781–782 (1984).
J. A. Ziemniak, R. G. Shank, and J. J. Schentag. Drug Metab. Dispos. 12:217–221 (1984).
H. Suzuki, Y. Sawada, Y. Sugiyama, T. Iga, and M. Hanano. J. Pharmacobiodyn. 8:73–76 (1985).
H. Suzuki, Y. Sawada, Y. Sugiyama, T. Iga, and M. Hanano. J. Pharmacol. Exp. Ther. 239:927–935 (1986).
S. R. Heisey, D. Held, and J. R. Pappenheimer. Am. J. Physiol. 203:775–781 (1962).
C. S. Kim, R. F. Keizer, W. W. Ambrose, and G. R. Breese Toxicol. Appl. Pharmacol. 90:436–444 (1987).
R. D. Myers. In R. D. Myers (ed.), Methods in Psychobiology, Academic Press, New York, 1972, pp. 169–221.
H. J. Bouman and T. B. Van Wimersma Greidanus. Brain Res. Bull. 4:575–577 (1979).
L. J. Pellegrino, A. S. Pellegrino, and A. J. Cushman. A Stereotaxic Atlas of the Rat Brain, Plenum Press, New York, 1979.
P. M. G. Bavin, A. Post, and J. E. Zarembo. Anal. Profiles Drug Substances 13:127–182 (1984).
M. Gibaldi and D. Perrier. Pharmacokinetics, 2nd ed. Marcel Dekker, New York, 1982.
H. J. Ross and E. M. Wright. Brain Res. 295:155–160 (1984).
A. V. Lorenzo and R. Spector. J. Pharmacol. Exp. Ther. 184:465–471 (1973).
J. T. Huang. Neurochem. Res. 7:1541–1548 (1982).
L. D. Prockop and L. S. Schanker. Life Sci. 4:141–149 (1962).
L. S. Schanker, L. D. Prockop, J. Schou, and P. Sisodia. Life Sci. 10:515–521 (1962).
V. A. Levin, J. Csejtey, and D. J. Byrd. Cancer Chemother. Pharmacol. 10:196–199 (1983).
V. A. Levin, D. Byrd, J. Campbell, R. L. Davis, and J. K. Borcich. Cancer Chemother. Pharmacol. 13:200–205 (1984).
G. Sarna, P. H. Hutson, and G. Curzon. J. Physicol. Paris 79:536–537 (1984).
V. A. Levin, D. Byrd, J. Campbell, D. D. Giannini, J. K. Borcich, and R. L. Davis. Cancer Res. 45:3803–3809 (1985).
V. A. Levin, D. Byrd, B. I. Sikic, B. B. Etiz, J. Campbell, J. K. Borcich, and R. L. Davis, Cancer Res. 45:3810–3815 (1985).
V. A. Levin and H. D. Landahl. J. Pharmacokin. Biopharm. 13:387–403 (1985).
L. G. Gisclon, F. M. Wong, and K. M. Giacomini. Am. J. Physiol. 253:F141–F150 (1987).
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Whittico, M.T., Giacomini, K.M. Cimetidine Elimination from the Cerebrospinal Fluid of the Rat. Pharm Res 5, 628–633 (1988). https://doi.org/10.1023/A:1015918802935
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DOI: https://doi.org/10.1023/A:1015918802935