title: The impact of P-glycoprotein mediated efflux on absorption of 11 sedating and less-sedating antihistamines using Caco-2 monolayers.
abstract: Caco-2 cells were used to compare P-gp mediated efflux and passive permeability using bidirectional transport of 11 antihistamines. An efflux ratio >2 indicated active efflux, with PSC833 and GF120918 used as functional P-gp inhibitors.        Antihistamines were measured directly by HPLC or LC/MS.        Fexofenadine had an efflux ratio of 37, yet had negligible passive permeability, even in the presence of a pH gradient (0.1 × 10(-6) cm/sec). Its precursor, terfenadine, had an efflux ratio of 2.5, while cetirizine, desloratadine and hydroxyzine were 4, 7 and 14, respectively. After incubation with P-gp inhibitors, these ratios dropped significantly. Loratadine, by contrast, had equivalent transport in both directions and passive permeability was high (24 × 10(-6) cm/sec). Dimenhydrinate was the only other sedating antihistamine to exhibit efflux, with a ratio of 10.        Gradient conditions of pH (6/7.4) increased efflux of terfenadine and desloratadine to over 31 and 38 fold respectively, yet this increased efflux was not associated with P-gp.        Altering functional P-gp in the gut is likely to influence absorption of some sedating antihistamines such as dimenhydrinate and hydroxyzine and most less-sedating antihistamines except loratadine. In addition, desloratadine exhibits pH dependent efflux which could further induce variable absorption of this antihistamine.
authors.affiliation: School of Pharmacy and Curtin Health Innovative Research Institute (CHIRI), Curtin University, Perth, Western Australia. a.p.crowe@curtin.edu.au
authors.forename: Andrew
authors.initials: A
authors.lastname: Crowe
authors.forename: Cameron
authors.initials: C
authors.lastname: Wright
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D001692:Biological Transport; D018938:Caco-2 Cells; D017332:Cetirizine / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D004347:Drug Interactions; D006634:Histamine H1 Antagonists / Q000378:metabolism / Q000493:pharmacokinetics*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007408:Intestinal Absorption; D017336:Loratadine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D013058:Mass Spectrometry; D010539:Permeability; D016593:Terfenadine / Q000031:analogs & derivatives / Q000493:pharmacokinetics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D006634:Histamine H1 Antagonists; D017336:Loratadine; D016593:Terfenadine; C093230:fexofenadine; C121345:desloratadine; D017332:Cetirizine