Stereoselective pharmacokinetics of cetirizine in the guinea pig: role of protein binding.
OBJECTIVE
To characterize the pharmacokinetics of cetirizine enantiomers in the guinea pig including protein binding in both the guinea pig and human plasma.


METHODS
Plasma concentrations of cetirizine enantiomers in the guinea pig were determined using a LC-MS/MS method after a short i.v. infusion (1, 2 and 4 mg/kg) of racemic cetirizine. Protein binding was determined using an in vitro equilibrium dialysis technique. A pharmacokinetic model was developed using NONMEM and the differences in pharmacokinetic parameters of levocetirizine and dextrocetirizine were estimated.


RESULTS
The plasma concentration time data of both the enantiomers were best described by a three-compartment pharmacokinetics model. The clearance (CL) of levocetirizine and dextrocetirizine was 1.2 and 2.7 ml/min, respectively, and the volume of distribution at steady state (Vss) was 457 ml and 996 ml, respectively. The fraction unbound (fu) in guinea pig plasma for levocetirizine and dextrocetirizine was 7-10% and 16-21% while in human plasma, it was 8% and 12%, respectively. The factor describing the difference in the pharmacokinetic parameters of the cetirizine enantiomers was estimated to be 2.26.


CONCLUSIONS
Cetirizine pharmacokinetics is stereoselective in the guinea pig. For levocetirizine, fu, CL and Vss were half those of dextrocetirizine, indicating that protein binding is an important factor affecting the pharmacokinetics of cetirizine. The effect of protein binding on the pharmacokinetics of the cetirizine enantiomers could be extrapolated to humans.
Gupta
Anubha
A
Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, Uppsala University, Box 591, SE-751 24 Uppsala, Sweden.
Hammarlund-Udenaes
Margareta
M
Chatelain
Pierre
P
Massingham
Roy
R
Jonsson
E Niclas
EN
D000818:Animals; D018926:Anti-Allergic Agents / Q000737:chemistry* / Q000493:pharmacokinetics*; D017332:Cetirizine / Q000737:chemistry* / Q000493:pharmacokinetics*; D003956:Dialysis; D006168:Guinea Pigs; D006801:Humans; D015233:Models, Statistical; D011485:Protein Binding; D013237:Stereoisomerism
D018926:Anti-Allergic Agents; D017332:Cetirizine