Abstract
To investigate the stereoselective distribution of methylphenidate (MPD) enantiomers in rats, the concentrations of each enantiomer were determined in plasma and brain regions (cerebellum, striatum, basal forebrain, brain stem, and cortex) after iv administration of racemic MPD and its individual enantiomers. The concentrations of MPD enantiomers in each brain region reached pseudo-steady state within 10 min after iv administration of racemic MPD (2 mg/kg dose). The influx clearances for MPD calculated from K Papp values in each brain region were not significantly different between MPD enantiomers and between the five brain regions. The mean K Papp values for (+ )-MPD in the striatum at 120 and 240 min after administration of racemic MPD were 10.1 and 10.5, respectively, and these values at each time were significantly larger than the K Papp values (7.5 and 7.0, respectively) for the (–)-isomer (P < 0.01). The K Papp value for (+ )-MPD in the striatum decreased by coadministration of mazindol as an inhibition of both dopamine and norepinephrine reuptake, but it was not changed by desipramine as a norepinephrine reuptake inhibitor. These results suggest that ( + )-MPD was bound specifically to the dopamine reuptake site in the striatum.
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REFERENCES
Y. L. Hurd and U. Ungerstedt. In vivo neurochemical profile of dopamine uptake inhibitor and releaser in rat caudate-putamen. Eur. J. Pharmacol. 166:251–260 (1989).
S. P. Butcher, J. Liptrot, and G. W. Aburyhnott. Characterization of methylphenidate and nomifensine induced dopamine release in rat striatum using in vivo brain microdialysis. Neurosci. Lett. 122:245–248 (1991).
J. A. Nielsen, D. S. Chapin, and K. E. Moore. Differential effects of d-amphetamine, β-phenylethylamine, cocaine and methylphenidate on the rate of dopamine synthesis in terminals of nigrostriatal and mesolimbic neurons and on the efflux of dopamine metabolites into cerebroventricular perfusates of rats. Life Sci. 33:1899–1907 (1983).
T. Zetterstrom, T. Sharp, A. K. Collin, and U. Ungerstedt. In vivo measurement of extracellular dopamine and DOPAC in rat striatum after various dopamine-released drugs; Implications for the origin of extracellular DOPAC. Eur. J. Pharmacol. 148:327–334 (1988).
R. A. Maxwell, E. Chaplin, S. B. Eckhardt, J. R. Soares, and G. Hite. Conformational similarities between molecular models of phenethylamine and of potent inhibitors of the uptake of tritiated norepinephrine by adrenergic nerves rabbit aorta. J. Pharmacol. Exp. Ther. 173:158–165 (1970).
K. S. Patrick, C. D. Kilts, and G. R. Breese. Pharmacology of the enantiomers of threo-methylphenidate. J. Pharmacol. Exp. Ther. 241:152–158 (1987).
A. Janowsky, M. M. Schweri, P. Berger, R. Long, P. Skolnick, and S. M. Paul. The effects of surgical and chemical lesion on striatal [3H]threo-(+)-methylphenidate binding: Correlation with [3H]dopamine uptake. Eur. J. Pharmacol. 108:487–491 (1985).
A. S. Units, T. M. Dawson, D. R. Gehlert, and J. K. Wamsley. Autoradiographic localization of [3H]methylphenidate binding sites in rat brain. Eur. J. Pharmacol. 113:146–155 (1986).
J. Glowinski and L. C. Iversen. Regional studies of catecholamines in the rat brain. I. The disposition of [3H]norepinephrine, [3H]dopamine and [3H]dopa in various regions of the brain. J. Neurochem. 13:655–669 (1966).
N. Takahashi, Y. Sawada, Y. Sugiyama, H. Suzuki, T. Iga, and M. Hanano. Kinetic analysis of in vivo dopamine reuptake function in mouse brain striatum by [3H]-mazindol. Xenobiot. Metab. Disp. 4:314–315 (1989).
E. Riva, P. D. Hrdina, and P. L. Morslli. Measurement of desipramine in brain tissue by a radioisotope derivative technique. J. Pharm. Pharmacol. 27:797–799 (1975).
T. Aoyama, H. Kotaki, and Y. Saitoh. Gas chromatographicmass spectrometric analysis of threo-methyphenidate enantiomers in plasma. J. Chromatogr. 494:420–423 (1989).
M. Gibaldi and D. Perrier. Drug and the Pharmaceutical Science, Vol. 15. Pharmacokinetics, 2nd ed., Marcel Dekker, New York, 1982, pp. 45–111, 199–219.
C. S. Patlak, R. G. Blasberg, and J. D. Fenstermacher. Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake date. J. Cereb. Blood Flow Metab. 3:1–7 (1983).
C. S. Patlak and R. G. Blasberg. Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake date. Generalization. J. Cereb. Blood Flow Metab. 5:584–590 (1983).
B. A. Fraj, Z. H. Israili, J. M. Perel, M. L. Jenkins, S. G. Holtzman, S. A. Cucinell, and P. G. Dayton. Metabolism and disposition of methylphenidate-14C: Studies in man and animals. J. Pharmacol. Exp. Ther. 191:535–547 (1974).
J. A. Javitch, S. M. Steittmatter, and S. H. Snyder. Differential visualization of dopamine and norepinephrine uptake site in rat brain using [3H]mazindol autoradiography. J. Neurosci. 5:1513–1517 (1985).
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Aoyama, T., Kotaki, H., Sawada, Y. et al. Stereospecific Distribution of Methylphenidate Enantiomers in Rat Brain: Specific Binding to Dopamine Reuptake Sites. Pharm Res 11, 407–411 (1994). https://doi.org/10.1023/A:1018917205292
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DOI: https://doi.org/10.1023/A:1018917205292