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Stereoselective pharmacokinetics of cetirizine in the guinea pig: Role of protein binding
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
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2006 (English)In: Biopharmaceutics & drug disposition, ISSN 0142-2782, E-ISSN 1099-081X, Vol. 27, no 6, 291-297 p.Article in journal (Refereed) Published
Abstract [en]

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, 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.

Place, publisher, year, edition, pages
2006. Vol. 27, no 6, 291-297 p.
Keyword [en]
pharmacokinetic, antihistamines, stereoselective, protein binding
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-94041DOI: 10.1002/bdd.509ISI: 000241129400005PubMedID: 16791848OAI: oai:DiVA.org:uu-94041DiVA: diva2:167736
Available from: 2006-03-03 Created: 2006-03-03 Last updated: 2011-06-01Bibliographically approved
In thesis
1. Role of the Blood-Brain Barrier in Stereoselective Distribution and Delay in H1 Receptor Occupancy of Cetirizine in the Guinea Pig Brain
Open this publication in new window or tab >>Role of the Blood-Brain Barrier in Stereoselective Distribution and Delay in H1 Receptor Occupancy of Cetirizine in the Guinea Pig Brain
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 51 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 27
Keyword
Pharmacokinetics/Pharmacotherapy, Cetirizine enantiomers, Brain distribution, Microdialysis, H1 receptor occupancy, Stereoselective-pharmacokinetics, Farmakokinetik/Farmakoterapi
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-6360 (URN)91-554-6468-8 (ISBN)
Public defence
2006-03-24, B42, BMC, Husargatan 3, Uppsala, 13:15
Opponent
Supervisors
Available from: 2006-03-03 Created: 2006-03-03Bibliographically approved

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