<p>Cetirizine, an H₁-antihistamine, is prescribed for allergic disorders. It exists as a racemic mixture, with levocetirizine being the active enantiomer. The central nervous system side-effects of H₁-antihistamines are caused by their penetration into the brain. In this thesis the plasma pharmacokinetics, transport across the blood-brain barrier (BBB) and H₁ receptor occupancy of cetirizine enantiomers was investigated <i>in vivo</i> in guinea pigs. The transport across the BBB was quantified using the microdialysis technique. Stereoselective brain distribution was investigated by measuring both unbound and total concentrations in plasma and brain. The time aspects of the H₁ receptor occupancy of levocetirizine was studied in the brain and the periphery.</p><p>The plasma pharmacokinetics of cetirizine was stereoselective with clearance and volume of distribution of levocetirizine being approximately half that of dextrocetirizine. This was mainly due to the differences in plasma protein binding of the enantiomers. The stereoselectivity in brain distribution indicated by the partition coefficient K_p (total AUC ratio brain to plasma) was caused by stereoselective plasma protein binding. The transport across the BBB measured in this thesis by the unbound partition coefficient K_p,uu (unbound AUC ratio brain to plasma) was the same for the two enantiomers. Binding within the brain was also not significantly different. The H₁ receptor occupancy of levocetirizine in brain lagged behind the plasma concentrations whereas it was not delayed with respect to the brain concentrations. This indicates that the delayed brain H₁ receptor occupancy of levocetirizine is caused by a slow transport across the BBB.</p><p>In summary, the results of this thesis emphasize the importance of measuring both the unbound and total concentrations in blood and brain to characterize stereoselective brain distribution. The thesis also emphasize the importance of taking local brain pharmacokinetics into consideration in understanding pharmacokinetic-pharmacodynamic relationships of drugs with central activity.</p>

Cetirizine, an H1-antihistamine, is prescribed for allergic disorders. It exists as a racemic mixture, with levocetirizine being the active enantiomer. The central nervous system side-effects of H1-antihistamines are caused by their penetration into the brain. In this thesis the plasma pharmacokinetics, transport across the blood-brain barrier (BBB) and H1 receptor occupancy of cetirizine enantiomers was investigated in vivo in guinea pigs. The transport across the BBB was quantified using the microdialysis technique. Stereoselective brain distribution was investigated by measuring both unbound and total concentrations in plasma and brain. The time aspects of the H1 receptor occupancy of levocetirizine was studied in the brain and the periphery. The plasma pharmacokinetics of cetirizine was stereoselective with clearance and volume of distribution of levocetirizine being approximately half that of dextrocetirizine. This was mainly due to the differences in plasma protein binding of the enantiomers. The stereoselectivity in brain distribution indicated by the partition coefficient Kp (total AUC ratio brain to plasma) was caused by stereoselective plasma protein binding. The transport across the BBB measured in this thesis by the unbound partition coefficient Kp,uu (unbound AUC ratio brain to plasma) was the same for the two enantiomers. Binding within the brain was also not significantly different. The H1 receptor occupancy of levocetirizine in brain lagged behind the plasma concentrations whereas it was not delayed with respect to the brain concentrations. This indicates that the delayed brain H1 receptor occupancy of levocetirizine is caused by a slow transport across the BBB. In summary, the results of this thesis emphasize the importance of measuring both the unbound and total concentrations in blood and brain to characterize stereoselective brain distribution. The thesis also emphasize the importance of taking local brain pharmacokinetics into consideration in understanding pharmacokinetic-pharmacodynamic relationships of drugs with central activity.