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Vol. 31, Issue 3, 312-318, March 2003
Pfizer Global Research and Development, Pfizer Inc., Groton,
Connecticut
The present study evaluates the impact of P-glycoprotein
(P-gp) on plasma-brain disposition and transepithelial transport of
sedating versus nonsedating H1-antagonists using multidrug-resistant (mdr) gene 1a and 1b
(mdr1a/b) knockout (KO) mice and human MDR1-transfected Madin-Darby canine kidney (MDCK) cells. Three nonsedating (cetirizine, loratadine, and desloratadine) and three sedating (diphenhydramine, hydroxyzine, and triprolidine) H1-antagonists were tested. Each compound was administered to KO and wild-type (WT) mice intravenously at 5 mg/kg. Plasma and brain drug concentrations were determined by
liquid chromatography-mass spectrometry analysis. Mean
pharmacokinetic parameters (CL, Vss, and
t1/2) were obtained using WinNonlin. In
addition, certirizine, desloratadine, diphenhydramine, and triprolidine
(2 µM) were tested as substrates for MDR1 using MDR1-MDCK cells. The
bidirectional apparent permeability was determined by measuring the
amount of compound at the receiving side at 5 h. The
brain-to-plasma area under the curve (AUC) ratio was 4-, 2-, and
>14-fold higher in KO compared with WT mice for cetirizine, loratadine, and desloratadine, respectively. In contrast, the brain-to-plasma AUC ratio between KO and WT was comparable for hydroxyzine, diphenhydramine, and triprolidine. Likewise, the efflux
ratio between basolateral to apical and apical to basolateral was 4.6- and 6.6-fold higher in MDR1-MDCK than the parental MDCK for certirizine
and desloratadine, respectively, whereas it was approximately 1 for
diphenhydramine and triprolidine. Our results demonstrate that sedating
H1-antagonists hydroxyzine, diphenhydramine, and triprolidine
are not P-gp substrates. In contrast, nonsedating H1-antagonists
cetirizine, loratadine, and desloratadine are P-gp substrates. Affinity
for P-gp at BBB may explain the lack of central nervous system side
effects of modern H1-antagonists.
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