DMD # 7211 1 Brain distribution of cetirizine enantiomers : Comparison of three different tissue - to - plasma partition coefficients : Kp , Kp , u , and Kp , uu

The objective of this study was to compare the blood-brain barrier (BBB) transport and brain distribution of levo (R-CZE) and dextrocetirizine (S-CZE). Methods: Microdialysis probes, calibrated using retrodialysis by drug, were placed into the frontal cortex and right jugular vein of eight guinea pigs. Racemic CZE (2.7 mg/kg) was administered as a 60 min i.v. infusion. Unbound and total concentrations of the enantiomers were measured in blood and brain with LC-MS/MS. The brain distribution of the CZE enantiomers were compared using the parameters Kp, Kp,u, Kp,uu and Vu,br. Kp compares total brain concentration to total plasma concentration, Kp,u compensates for binding in plasma whereas Kp,uu compensates for binding also within the brain tissue and directly quantifies the transport across the BBB. Vu,br describes binding within the brain. Results and Conclusions: The stereoselective brain distribution indicated by the Kp of 0.22 and 0.04 for Sand R-CZE, respectively, was caused by different binding to plasma proteins. The transport of the CZE enantiomers across the BBB was not stereoselective as the Kp,uu was 0.17 and 0.14 (ns) for S and R-CZE, respectively. The Kp,uu values show that the enantiomers are effluxed to a large extent across the BBB. The Vu,br of approximately 2.5 ml/g brain was also similar for both the enantiomers and the value indicates high binding to brain tissue. Thus, when determining stereoselectivity in brain distribution it is important to study all factors governing this distribution, binding in blood and brain, and the BBB equilibrium. This article has not been copyedited and formatted. The final version may differ from this version. DMD Fast Forward. Published on November 22, 2005 as DOI: 10.1124/dmd.105.007211 at A PE T Jornals on Jne 3, 2017 dm d.aspurnals.org D ow nladed from