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Sotalol Permeability in Cultured-Cell, Rat Intestine, and PAMPA System

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ABSTRACT

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 (Papp) 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.

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Abbreviations

BCS:

Biopharmaceutics Classification System

BDDCS:

Biopharmaceutics Drug Disposition Classification System

FBS:

fetal bovine serum

HBSS:

Hank’s balanced salt solution

MDCK:

Madin Darby canine kidney

MDR-1 (P-gp):

multidrug resistance -1 (P-glycoprotein)

PAMPA:

parallel artificial membrane permeability assay

TEER:

transepithelial electrical resistance

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ACKNOWLEDGMENTS & DISCLOSURES

We thank the Chinese Scholarship Council for providing financial support for Wei Liu to study and carry out a portion of these studies in Dr. Benet’s laboratory at the University of California, San Francisco. The studies in Dr. Benet’s lab were funded in part by NIH grant RR031474.

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Authors and Affiliations

  1. Department of Pharmacy, Peking University Third Hospital, Beijing, 100191, China

    Wei Liu, Leslie Z. Benet & Suo-Di Zhai

  2. Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, 94143, USA

    Wei Liu, Hideaki Okochi & Leslie Z. Benet

Authors
  1. Wei Liu
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  2. Hideaki Okochi
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  3. Leslie Z. Benet
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  4. Suo-Di Zhai
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Correspondence to Suo-Di Zhai.

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Liu, W., Okochi, H., Benet, L.Z. et al. Sotalol Permeability in Cultured-Cell, Rat Intestine, and PAMPA System. Pharm Res 29, 1768–1774 (2012). https://doi.org/10.1007/s11095-012-0699-3

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  • DOI: https://doi.org/10.1007/s11095-012-0699-3

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