P-Glycoprotein Limits the Brain Penetration of Nonsedating but not Sedating H1-Antagonists

Abstract

ABSTRACT: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, V ss , and t 1/2 ) were obtained using WinNonlin. In addition, certirizine, desloratadine, diphenhydramine, and triprolidine (2 M) 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.Antagonists of H1 histamine receptors (H1-antagonists) are the mainstays of treatment for a number of allergic disorders, particularly rhinitis, conjunctivitis, dermatitis, urticaria, and asthma. Two generations of H1-antagonists have been developed so far. The first generation H1-antagonists such as diphenhydramine (Benadryl), triprolidine (Actifed), or hydroxyzine (Atarx) produce histamine blockade at H1-receptors in the central nervous system (CNS 1 ) and frequently cause somnolence or other CNS adverse effects (Simons, 1999). Therefore, the first generation H1-antagonists are also referred to as sedating antihistamines. The second generation H1-antagonists such as cetirizine (Zyrtec), loratadine (Claritin), fexofenadine (Allegra), or desloratadine (Clarinex) represent an advance in therapeutics; in manufacturers' recommended doses, they produce relatively little somnolence or other CNS side effects (Kay and Harris, 1999). Therefore, the second generation H1-antagonists are frequently referred as nonsedating antihistamines. Evidence for this improvement in tolerance profile resulting from reduced CNS penetration has been li...

Influx and Efflux Transport of H1-Antagonist Epinastine Across the Blood-Brain Barrier

“…The absence of a sedative effect of desloratadine may be explained by efficient efflux via P-gp, as demonstrated previously (Chen et al, 2003), that negates the uptake by the BCECs. Nonsedative fexofenadine was reported to show relatively low transport via P-gp, as evaluated in terms of the flux ratio of basal-to-apical/apical-to-basal transport in a monolayer of MDR1-expressing cells, although it is a substrate of P-gp (Cvetkovic et al, 1999).…”

“…Since the cationic derivatives also exhibit stronger sedative effects, the influx transporter was supposed to be a determinant of the sedative effect of H1-antagonists (Yamazaki et al, 1994a,b,c). Then, involvement of the efflux transporter P-gp as a determinant was proposed, and several studies found a positive correlation between the sedative effect and transport by P-gp (Cvetkovic et al, 1999;Tamai et al, 2000a;Chishty et al, 2001;Chen et al, 2003). Accordingly, both influx and efflux transporters should be important to determine the apparent brain distribution of H1-antagonists.…”

“…Several influx and efflux transporters, including P-glycoprotein (P-gp), multidrug resistance-associated proteins (MRPs), monocarboxylic acid transporter, and organic cation transporter, have been identified in BCECs (Tamai and Tsuji, 2000b), and the differential CNS side effects among H1-antagonists may be associated with differences of BBB permeability via these transporters. Recently, it was reported that some nonsedative second-generation H1-antagonists are substrates of P-gp, and the involvement of P-gp in efflux transport at the BBB may explain their limited brain distributions (Cvetkovic et al, 1999;Tamai et al, 2000a;Chishty et al, 2001;Chen et al, 2003). Furthermore mepyramine, a classical sedative H1-antagonist, is taken up by the BCECs via a carrier-mediated transport system (Yamazaki et al, 1994a,b,c;Tamai et al, 2000a).…”

The Effects of Cetirizine on P-glycoprotein Expression and Function In vitro and In situ

“…Western blotting results of present study confirm the idea. On the other hand, previous studies demonstrated P-gp substrate role of the cetirizine in mice blood-brain barrier (BBB), 20 1b (mdr1a/b) knockout mice, 21 human MDR1-transfected Madin-Darby canine kidney cells, 21 and human Caco-2 cells 22 using monolayer efflux assay 20 and other in vitro and in situ assays. To the best of our knowledge, both digoxin and cetirizine are substrates of P-gp and competition for binding sites of P-gp molecules by them is suggested.…”

Pharmacology of Antihistamines

“…A major reason for the reduced penetration of second-generation H 1 -antihistamines into the brain is because their translocation across the blood-brain barrier is under the control of active transporter proteins, of which the ATP-dependent efflux pump, P-glycoprotein, is the best known[50,51]. It also became apparent that antihistamines differ in their substrate specificity for P-glycoprotein, fexofenadine being a particularly good substrate[52].…”