title: In vitro, ex vivo and in vivo examination of buccal absorption of metoprolol with varying pH in TR146 cell culture, porcine buccal mucosa and Göttingen minipigs.
abstract: This work studied the buccal absorption of metoprolol in vitro, ex vivo and in vivo as a function of buffered pH at 7.4, 8.5, 9.0 and 9.5. Permeability studies showed a correlation (r(2)=0.92) between in vitro TR146 cell culture and ex vivo porcine buccal mucosa in a modified Ussing chamber. A higher apparent permeability was observed at higher pH values, i.e. the more compound that was unionised the higher the permeability. In vivo studies were conducted in anaesthetised Göttingen mini-pigs. A clear influence of pH on the absorption was seen and a significant higher absolute bioavailability was obtained after buccal dosing (58-107%) compared to oral (3%) administration, ranging 58-107% and 3%, respectively. Macroscopically, no local toxic effects were observed by visual inspection of mini-pig cheeks. A very clear level C in vitro in vivo correlation (r(2)=0.98) was obtained between the observed in vitro permeabilities and the bioavailability observed in vivo, suggesting that the two in vitro models have good predictive power for drug delivery, which could be a useful tool for future formulation developments intended for buccal delivery.
authors.affiliation: Biologics and Pharmaceutical Science, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark. rhol@lundbeck.com
authors.forename: René
authors.initials: R
authors.lastname: Holm
authors.forename: Emil
authors.initials: E
authors.lastname: Meng-Lund
authors.forename: Morten B
authors.initials: MB
authors.lastname: Andersen
authors.forename: Mads L
authors.initials: ML
authors.lastname: Jespersen
authors.forename: Jens-Jacob
authors.initials: JJ
authors.lastname: Karlsson
authors.forename: Mats
authors.initials: M
authors.lastname: Garmer
authors.forename: Erling B
authors.initials: EB
authors.lastname: Jørgensen
authors.forename: Jette
authors.initials: J
authors.lastname: Jacobsen
mesh_terms: D000042:Absorption; D000818:Animals; D001682:Biological Availability; D002460:Cell Line; D005782:Gels; D006801:Humans; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008297:Male; D008790:Metoprolol / Q000097:blood / Q000493:pharmacokinetics*; D009061:Mouth Mucosa / Q000378:metabolism*; D013552:Swine
chemical_list: D005782:Gels; D008790:Metoprolol