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Sotalol permeability in cultured-cell, rat intestine, and PAMPA system
Wei Liu1, Hideaki Okochi, Leslie Z Benet
1Department of Pharmacy, Peking University Third Hospital, Beijing 100191, China.
Purpose:
To clarify sotalol's classification in the BCS versus BDDCS systems through cellular, rat everted sac and PAMPA permeability studies.
Methods:
Studies were carried out in Madin Darby canine kidney (MDCK) and MDR1-transfected MDCK (MDCK-MDR1) cell lines, rat everted gut sacs and the Parallel Artificial Membrane Permeability Assay (PAMPA) system. Three-hour transport studies were conducted in MDCK cell lines (with apical pH changes) and MDCK-MDR1 cells (with and without the P-glycoprotein inhibitor GG918); male Sprague-Dawley rats (300~350 g) were used to prepare everted sacs. In the PAMPA studies, drug solutions at different pH's were dosed in each well and incubated for 5 h. Samples were measured by LC-MS/MS, or liquid scintillation counting and apparent permeability (P(app)) was calculated.
Results:
Sotalol showed low permeability in all of the cultured-cell lines, everted sacs and PAMPA systems. It might be a border line P-glycoprotein substrate. The PAMPA study showed that sotalol's permeability increased with a higher apical pH, while much less change was found in MDCK cells.
Conclusion:
The low permeability rate for sotalol correlates with its Class 3 BDDCS assignment and lack of in vivo metabolism.
