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Stereoselective pharmacokinetics of cetirizine in the guinea pig: role of protein binding
Author(s) -
Gupta Anubha,
HammarlundUdenaes Margareta,
Chatelain Pierre,
Massingham Roy,
Jonsson E. Niclas
Publication year - 2006
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.509
Subject(s) - cetirizine , pharmacokinetics , chemistry , enantiomer , levocetirizine , pharmacology , volume of distribution , guinea pig , medicine , stereochemistry , endocrinology
Purpose . 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 ( V ss ) was 457 ml and 996 ml, respectively. The fraction unbound ( f u ) 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, f u , CL and V ss 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. Copyright © 2006 John Wiley & Sons, Ltd.