Abstract
This investigation studied the possible effect of different iv administration rates (bolus and infusions) of eliprodil, a new anti-ischemic agent, on the drug distribution in various body compartments. Following bolus administration of a 15-mg kg−1 dose, plasma concentrations were best fitted by a 3-compartment open model of t1/2α=14 sec, t1/2β=4 min, and t1/3γ=1.8 hr. Plasma and heart Cmax values were lowered by decreasing the infusion rate (the 15-mg dose was administered in 15 or 60 min) whereas brain Cmax values were not modified. In contrast, AUC values did not depend upon the rate of infusion. The present findings may have important implications in relating tissue concentrations with the desired therapeutic effect as well as with the side effects of the drug at its sites of action within brain and heart. The use of a simplified model built with plasma and tissue kinetic parameters following bolus injection allows one to predict the amount of drug present in the organs according to the mode of administration, but not the evolution of tissue to plasma ratio during the infusions.
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References
M. Gibaldi. Effect of mode of administration on drug distribution in a two-compartment open system.J. Pharm. Sci. 58:327–331 (1969).
P. A. Miglioli. Tissue diffusion of doxycycline in rats: A comparison between intravenous bolus injection or drip-infusion.Chemotherapia 7:156–159 (1988).
V. R. Liguori, J. J. Giglio, E. Miller, and R. D. Sullivan. Effects of different dose schedules of amethopterin on serum and tissue concentrations and urinary excretion patterns.Clin. Pharmacol. Ther. 3:34–40 (1962).
P. A. Miglioli, V. Businaro, F. Manoni, and T. Berti. Tissue distribution of methotrexate in rats. A comparison between intravenous injection as bolus or drip infusion.Drugs Exp. Clin. Res. 11:275–279 (1985).
K. Nooter, P. Sonneveld, A. Martens, A. Hagenbeek, and F. Schultz. Tissue distribution and meylotoxicity of daunomycin in the rat: Rapid bolus injection vs. continuous infusion.Eur. J. Cancer Clin. Oncol. 22:801–806 (1986).
S. H. Powell, W. L. Thompson, M. A. Luthe, R. C. Stern, D. A. Grossniklaus, D. D. Bloxham, D. L. Groden, M. R. Jacobs, A. O. Discenna, H. A. Cash, and J. D. Klinger. Once-daily versus continuous aminoglycoside dosing: efficacy and toxicity in animal and clinical studies of gentamicin, netilmicin and tobramycin.J. Infect. Dis. 147:918–932 (1983).
C. A. Woods, D. R. Norton, S. J. Kohlepp, P. W. Kohnen, G. A. Porter, D. C. Houghton, R. E. Brummett, W. M. Bennett, and D. N. Gilbert. The influence of tobramycin dosage regimens on nephrotoxicity, ototoxicity, and antibacterial efficacy in a rat model of subcutaneous abcess.J. Infect. Dis. 158:13–22 (1988).
R. Parti and W. Wolf. Quantitative subcellular distribution of platinum in rat tissues following i.v. bolus and i.v. infusion of cisplatin.Cancer Chemother. Pharmacol. 26:188–192 (1990).
D. A. Uccellini, K. Raymond, and D. J. Morgan. Influence of intravenous infusion duration on the tissue concentration profile.J. Pharmacokin. Biopharm. 14:323–334 (1986).
C. J. Carter, J. P. Rivy, and B. Scatton. Ifenprodil and SL 82.0715 are antagonists at the polyamine site of theN-methyl-d-aspartate (NMDA) receptor.Eur. J. Pharmacol. 164:611–612 (1989).
C. J. Carter, K. G. Lloyd, B. Zivkovic, and B. Scatton. Ifenprodil and SL 82.0715 as cerebral anti-ischemic agents. III. Evidence for antagonist effects at the polyamine modulatory site within the NMDA receptor complex.J. Pharmacol. Exp. Ther. 253:475–482 (1990).
B. Gotti, J. Benavides, E. T. MacKenzie, and B. Scatton. The pharmacotherapy of focal cortical ischemia in the mouse.Brain Res. 522:290–307 (1990).
S. Tudela, A. Rouchouse, and A. Durand. Sensitive assay of SL 82.0715 in plasma by microbore HPLC with amperometric detection. Abstract. 19th International Symposium on Chromagraphy, Sept. 1992, Aix en Provence, France.
B. Richmond, P. Vescuso, and S. Peterson. A business user's guide to STELLA. High Performance Systems, Inc., Lyme, NH, 1987.
C. Washington, N. Washington, and C. G. Wilson.Pharmacokinetic Modelling Using STELLA on the Apple Macintosh. In L. A. Damani (ed.), Ellis Horwood, London, 1990.
K. Ahmad and F. Medzihradsky. Distribution of lidocaïne in blood and tissue after single doses and steady infusion.Res. Commun. Chem. Pathol. Pharmacol. 2:813–828 (1971).
P. A. Miglioli and M. T. Dorigo. Diffusibilita del cefuroxim nell'umor acqueo ed in altri fluidi di ratti e conigli. InL'Evoluzione della Antibiotico Terapia Beta-Lattamina: Le Metossimine. Proceedings of an international meeting, April 1980. Masson, Italia, Rome.
R. Franco, A. Bonaccorsi, M. G. Castelli, S. Garattini, and P. L. Morselli. Relationships between chronotropic effect, 1-3H-Noradrenaline uptake and tissue concentrations of desipramine, protriptyline and doxepin in rat isolated atria.Arch. Int. Pharmacodyn. Ther. 224:55–65 (1976).
G. Bianchetti, A. Bonaccorsi, A. Chiodaroli, R. Franco, S. Garattini, R. Gomeni, and P. L. Morselli. Plasma concentrations and cardiotoxic effects of desipramine and protriptyline in the rat.Br. J. Pharmacol. 60:11–19 (1977).
A. Bonaccorsi, R. Franco, S. Garattini, P. L. Morselli, and E. Pita. Plasma nortriptyline and cardiac responses in young and old rats.Br. J. Pharmacol. 60:21–27 (1977).
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Garrigou-Gadenne, D., Thenot, JP. & Morselli, P.L. Influence of the rate of intravenous administration of eliprodil (SL 82.0715), a new anti-ischaemic agent, on its distribution in rat plasma and tissues. Journal of Pharmacokinetics and Biopharmaceutics 23, 147–161 (1995). https://doi.org/10.1007/BF02354269
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DOI: https://doi.org/10.1007/BF02354269