Abstract
Cetirizine (Zyrtec®) is a racemic mixture of two enantiomers, levocetirizine (Xyzal®) (L) and dextrocetirizine (D), which display different binding properties for human H1 histamine receptor. L displays a 30-fold higher affinity for H1 receptors than D (pKi = 8.5 and 7.1, respectively) due to the much slower dissociation kinetics of L. The half time of dissociation (t½) from human H1 receptors is 142 min for L and 6 min for D. Similar stereoselectivity is observed in isolated organs: L inhibits histamine induced ileum and trachea contractions in guinea pig with a 16 to 30-fold higher potency than D. The difference in t½ from H1 receptors is also reflected by the slow recovery of histamine contractions when the ileum is exposed to L compared to D. It takes more than 160 min to recover 50% of the maximal histamine induced contraction after removal of L from the organ bath and only 11 min after removal of D. With human liver microsomes, the intrinsic clearance (Cl) describing the formation of metabolites is higher for D. In healthy volunteers, the plasma elimination half-life is shorter for D (5.5 h) than for L (7.8 h), the volume of distribution (V/F), the total body Cl, the renal Cl and the metabolic Cl are higher for D. The % dose eliminated unchanged in 48 h urine is higher for L (73%) than for D (64%) indicating a higher absolute bioavailability for L. In conclusion, not only is L the eutomer but its disposition characteristics are favourable in comparison with D.