Received for publication September 6, 2005.
Revised November 18, 2005.
Accepted for publication November 18, 2005.

Brain distribution of cetirizine enantiomers: Comparison of three different tissue-to-plasma partition coefficients: K_p, K_p,u, and K_p,uu

Abstract

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 K_p, K_p,u, K_p,uu and V_u,br. K_p compares total brain concentration to total plasma concentration, K_p,u compensates for binding in plasma whereas K_p,uu compensates for binding also within the brain tissue and directly quantifies the transport across the BBB. V_u,br describes binding within the brain. Results and Conclusions: The stereoselective brain distribution indicated by the K_p of 0.22 and 0.04 for S- and 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 K_p,uu was 0.17 and 0.14 (ns) for S and R-CZE, respectively. The K_p,uu values show that the enantiomers are effluxed to a large extent across the BBB. The V_u,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.

Key words: blood-brain barrier, blood-CNS transport, CNS pharmacokinetics, distribution, drug efflux, membrane transport, pharmacokinetics, protein binding

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