TY - JOUR T1 - Population Pharmacokinetic Modeling of Blood-Brain Barrier Transport of Synthetic Adenosine A<sub>1</sub> Receptor Agonists JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 1138 LP - 1146 DO - 10.1124/jpet.104.071308 VL - 311 IS - 3 AU - M. P. Schaddelee AU - D. Groenendaal AU - J. DeJongh AU - C. G. J. Cleypool AU - A. P. IJzerman AU - A. G. De Boer AU - M. Danhof Y1 - 2004/12/01 UR - http://jpet.aspetjournals.org/content/311/3/1138.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -