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Metformin Transport in Native MDCK-Wt and MDCK-II Monolayers Unveils Functional Inter-Strains Differences Influencing Drug Permeability.
Pharm Res. 2020 Jun 08; 37(7):121.PR

Abstract

PURPOSE

MDCK cells are commonly used to assess drug permeability, but the existence of various strains merits a comparative functional study. Since metformin absorption is largely mediated by transporters and paracellular diffusion, we used it to functionally compare MDCK-wt and MDCK-II.

METHODS

Uptake, bidirectional transport and efflux experiments were performed using different buffers, pH, and a panel of transporter inhibitors. Relative contributions to total transport in both strains were estimated.

RESULTS

Metformin uptake into MDCK-wt was linear but saturable in MDCK-II. Uptake into MDCK-wt or -II was promoted at pH 5.4 or 8.4, respectively. Quinidine and cimetidine similarly inhibited uptake in both strains. Lopinavir (PMAT specific) at pH 5.4 or pyrimethamine (MATE specific) at pH 8.4 differentially inhibited MDCK-wt or -II, respectively. Transport at pH 7.4 was absorptive regardless of strains, but secretory (MDCK-II) or absorptive (MDCK-wt) at pH 5.4. Efflux was largely basolateral in both strains. While paracellular permeability was similar between strains, total transport was dominated by transporters in MDCK-II or paracellular diffusion in MDCK-wt.

CONCLUSIONS

Metformin transport revealed functional differences between MDCK strains. Apical uptake was governed by MATE in MDCK-II or PMAT in MDCK-wt, such that metformin transport was either secretory or absorptive, respectively.

Authors+Show Affiliations

Department of Biopharmaceutics and Pharmaceutical Technology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany. Departamento de Farmacia, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Santiago, Chile.Departamento de Farmacia, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Santiago, Chile. Innovation and Biopharmaceutical Evaluation Center (IBECenter), Av. Mexico, #715, Recoleta, Santiago, Chile.Innovation and Biopharmaceutical Evaluation Center (IBECenter), Av. Mexico, #715, Recoleta, Santiago, Chile. pgonzalez@ibe-center.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32514792

Citation

García, Mauricio A., et al. "Metformin Transport in Native MDCK-Wt and MDCK-II Monolayers Unveils Functional Inter-Strains Differences Influencing Drug Permeability." Pharmaceutical Research, vol. 37, no. 7, 2020, p. 121.
García MA, Contreras D, González PM. Metformin Transport in Native MDCK-Wt and MDCK-II Monolayers Unveils Functional Inter-Strains Differences Influencing Drug Permeability. Pharm Res. 2020;37(7):121.
García, M. A., Contreras, D., & González, P. M. (2020). Metformin Transport in Native MDCK-Wt and MDCK-II Monolayers Unveils Functional Inter-Strains Differences Influencing Drug Permeability. Pharmaceutical Research, 37(7), 121. https://doi.org/10.1007/s11095-020-02824-w
García MA, Contreras D, González PM. Metformin Transport in Native MDCK-Wt and MDCK-II Monolayers Unveils Functional Inter-Strains Differences Influencing Drug Permeability. Pharm Res. 2020 Jun 8;37(7):121. PubMed PMID: 32514792.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Metformin Transport in Native MDCK-Wt and MDCK-II Monolayers Unveils Functional Inter-Strains Differences Influencing Drug Permeability. AU - García,Mauricio A, AU - Contreras,Danae, AU - González,Pablo M, Y1 - 2020/06/08/ PY - 2020/02/25/received PY - 2020/04/14/accepted PY - 2020/6/10/entrez KW - MDCK cells KW - metformin KW - paracellular KW - permeability KW - transporters SP - 121 EP - 121 JF - Pharmaceutical research JO - Pharm. Res. VL - 37 IS - 7 N2 - PURPOSE: MDCK cells are commonly used to assess drug permeability, but the existence of various strains merits a comparative functional study. Since metformin absorption is largely mediated by transporters and paracellular diffusion, we used it to functionally compare MDCK-wt and MDCK-II. METHODS: Uptake, bidirectional transport and efflux experiments were performed using different buffers, pH, and a panel of transporter inhibitors. Relative contributions to total transport in both strains were estimated. RESULTS: Metformin uptake into MDCK-wt was linear but saturable in MDCK-II. Uptake into MDCK-wt or -II was promoted at pH 5.4 or 8.4, respectively. Quinidine and cimetidine similarly inhibited uptake in both strains. Lopinavir (PMAT specific) at pH 5.4 or pyrimethamine (MATE specific) at pH 8.4 differentially inhibited MDCK-wt or -II, respectively. Transport at pH 7.4 was absorptive regardless of strains, but secretory (MDCK-II) or absorptive (MDCK-wt) at pH 5.4. Efflux was largely basolateral in both strains. While paracellular permeability was similar between strains, total transport was dominated by transporters in MDCK-II or paracellular diffusion in MDCK-wt. CONCLUSIONS: Metformin transport revealed functional differences between MDCK strains. Apical uptake was governed by MATE in MDCK-II or PMAT in MDCK-wt, such that metformin transport was either secretory or absorptive, respectively. SN - 1573-904X UR - https://www.unboundmedicine.com/medline/citation/32514792/Metformin_Transport_in_Native_MDCK-Wt_and_MDCK-II_Monolayers_Unveils_Functional_Inter-Strains_Differences_Influencing_Drug_Permeability L2 - https://doi.org/10.1007/s11095-020-02824-w DB - PRIME DP - Unbound Medicine ER -
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