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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on August 3, 2004; DOI: 10.1124/jpet.104.071308

0022-3565/04/3113-1138-1146$20.00
JPET 311:1138-1146, 2004
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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Population Pharmacokinetic Modeling of Blood-Brain Barrier Transport of Synthetic Adenosine A1 Receptor Agonists

M. P. Schaddelee1, D. Groenendaal, J. DeJongh, C. G. J. Cleypool, A. P. IJzerman, A. G. De Boer, and M. Danhof

Divisions of Pharmacology (M.P.S., D.G., J.D., C.G.J.C., A.G.D.B., M.D.) and Medicinal Chemistry (A.P.IJ.), Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands

A population pharmacokinetic model is proposed for estimation of the brain distribution clearance of synthetic A1 receptor agonists in vivo. Rats with permanent venous and arterial cannulas in combination with a microdialysis probe in the striatum received intravenous infusions of 8-methylamino-N6-cyclopentyladenosine (MCPA) and 2'-deoxyribose-N6-cyclopentyladenosine (2'-dCPA) (10 mg kg-1). The clearance for transport from blood to the brain was estimated by simultaneous analysis of the blood and extracellular fluid concentrations using a compartmental pharmacokinetic model. The proposed pharmacokinetic model consists of three compartments describing the time course of the concentration in blood in combination with three compartments for the brain extracellular fluid concentrations. The blood clearance was 7.4 ± 0.5 for MCPA and 7.2 ± 1.4 ml min-1 for 2'-dCPA. The in vivo microdialysis recoveries determined by the dynamic-no-net-flux method were independent of time with values of 0.21 ± 0.02 and 0.22 ± 0.01 for MCPA and 2'-dCPA, respectively. The values of the intercompartmental clearance for the distribution from blood to brain were 1.9 ± 0.4 versus 1.6 ± 0.3 µl min-1 for MCPA and 2'-dCPA, respectively. It is concluded that on basis of the novel six-compartment model precise estimates of the rate of brain distribution are obtained that are independent of eventual differences in systemic exposure. The low brain distribution rates of MCPA and 2'-dCPA were consistent with in vitro tests. Furthermore, a slow elimination from the brain compartment was observed, indicating that the duration of central nervous system effects may be much longer than expected on the basis of the terminal half-life in blood.

Received May 12, 2004; accepted July 23, 2004.

Address correspondence to: Dr. Meindert Danhof, Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands. E-mail: m.danhof{at}lacdr.leidenuniv.nl






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