The impact of P-glycoprotein mediated efflux on absorption of 11 sedating and less-sedating antihistamines using Caco-2 monolayers.
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Crowe A, Wright C
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.
- PubMed ID
- 22188412 [ View in PubMed]
- 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 x 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 x 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.
DrugBank Data that Cites this Article
- Drugs
- Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Hydroxyzine P-glycoprotein 1 Protein Humans UnknownSubstrateDetails