The impact of P-glycoprotein mediated efflux on absorption of 11 sedating and less-sedating antihistamines using Caco-2 monolayers

Xenobiotica. 2012 Jun;42(6):538-49. doi: 10.3109/00498254.2011.643256. Epub 2011 Dec 22.


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.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / physiology*
  • Biological Transport
  • Caco-2 Cells
  • Cetirizine / pharmacokinetics
  • Chromatography, High Pressure Liquid
  • Drug Interactions
  • Histamine H1 Antagonists / metabolism
  • Histamine H1 Antagonists / pharmacokinetics*
  • Humans
  • Hydrogen-Ion Concentration
  • Intestinal Absorption
  • Loratadine / analogs & derivatives
  • Loratadine / pharmacokinetics
  • Mass Spectrometry
  • Permeability
  • Terfenadine / analogs & derivatives
  • Terfenadine / pharmacokinetics


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Histamine H1 Antagonists
  • Loratadine
  • Terfenadine
  • fexofenadine
  • desloratadine
  • Cetirizine