MDCK (Madin-Darby Canine Kidney) Cells: A Tool for Membrane Permeability Screening

Irvine, Jennifer D.; Takahashi, Lori H.; Lockhart, Karen; Cheong, Jonathan; Tolan, John W.; Selick, Harold E.; Grove, Jeffrey

doi:10.1021/js9803205

Cited by 834 publications

(557 citation statements)

References 33 publications

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“…(27). In contrast, the collecting duct-derived MadinDarby canine kidney (MDCK) cell line is routinely used for drug permeability and transport studies (following transfection with specific human drug transporters), typically in the context of oral drug absorption and brain penetration (28). Similarly, Caco-2 cells are widely used as an in vitro model of intestinal, as well as blood-brain barrier permeability, and have recently been proposed as a possible in vitro model of passive renal tubular reabsorption (29).…”

Section: Measurement Of Renal Passive Tubular Permeability In Vitromentioning

confidence: 99%

Key to Opening Kidney for In Vitro–In Vivo Extrapolation Entrance in Health and Disease: Part I: In Vitro Systems and Physiological Data

Scotcher

Jones²,

Posada

et al. 2016

AAPS J

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ABSTRACT.The programme for the 2015 AAPS Annual Meeting and Exhibition (Orlando, FL; 25-29 October 2015) included a sunrise session presenting an overview of the state-of-the-art tools for in vitro-in vivo extrapolation (IVIVE) and mechanistic prediction of renal drug disposition. These concepts are based on approaches developed for prediction of hepatic clearance, with consideration of scaling factors physiologically relevant to kidney and the unique and complex structural organisation of this organ. Physiologically relevant kidney models require a number of parameters for mechanistic description of processes, supported by quantitative information on renal physiology (system parameters) and in vitro/in silico drug-related data. This review expands upon the themes raised during the session and highlights the importance of high quality in vitro drug data generated in appropriate experimental setup and robust system-related information for successful IVIVE of renal drug disposition. The different in vitro systems available for studying renal drug metabolism and transport are summarised and recent developments involving state-of-the-art technologies highlighted. Current gaps and uncertainties associated with system parameters related to human kidney for the development of physiologically based pharmacokinetic (PBPK) model and quantitative prediction of renal drug disposition, excretion, and/or metabolism are identified.

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Section: Measurement Of Renal Passive Tubular Permeability In Vitromentioning

confidence: 99%

Key to Opening Kidney for In Vitro–In Vivo Extrapolation Entrance in Health and Disease: Part I: In Vitro Systems and Physiological Data

Scotcher

Jones²,

Posada

et al. 2016

AAPS J

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“…represents the flux across the monolayer (permeability rate), A (cm 2 ) the surface area of the monolayer, V (cm 3 ) the volume of the receiver chamber, and C o (μmol/L) the initial concentration in the donor compartment (25). Results are presented as mean P app ± SD (n = 3).…”

Section: Transport Assaysmentioning

confidence: 99%

Breast Cancer Resistance Protein and P-glycoprotein Limit Sorafenib Brain Accumulation

Lagas

Waterschoot

Sparidans

et al. 2010

Molecular Cancer Therapeutics

165

123

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Sorafenib is a second-generation, orally active multikinase inhibitor that is approved for the treatment of patients with advanced renal cell carcinoma and patients with unresectable hepatocellular carcinoma. We studied active transport of sorafenib in MDCK-II cells expressing human P-glycoprotein (P-gp/ABCB1) or ABCG2 (breast cancer resistance protein) or murine Abcg2. Sorafenib was moderately transported by P-gp and more efficiently by ABCG2 and Abcg2. Because sorafenib is taken orally, we orally administered sorafenib to wild-type, Abcb1a/1b −/− , Abcg2 −/− , and Abcb1a/1b;Abcg2 −/− mice, completely lacking functional Abcb1a/1b, Abcg2, or both, respectively, and we studied plasma pharmacokinetics and brain accumulation. The systemic exposure on oral administration was not different among all strains. However, brain accumulation was 4.3-fold increased in Abcg2 −/− mice and 9.3-fold increased in Abcb1a/1b;Abcg2 −/− mice. Moreover, when wildtype mice were treated with sorafenib in combination with the dual P-gp and ABCG2 inhibitor elacridar, brain accumulation was similar to that observed for Abcb1a/1b;Abcg2 −/− mice. These results show that the brain accumulation of sorafenib is primarily restricted by ABCG2. This contrasts with previous studies using shared ABCG2 and P-gp substrates, which all suggested that P-gp dominates at the blood-brain barrier, and that an effect of ABCG2 is only evident when both transporters are absent. Interestingly, for sorafenib, it is the other way around, that is, ABCG2, and not P-gp, plays the dominant role in restricting its brain accumulation. Clinically, our findings may be relevant for the treatment of renal cell carcinoma patients with central nervous system relapses, as a dual ABCG2 and P-gp inhibitor might improve the central nervous system entry and thereby the therapeutic efficacy of sorafenib. Mol Cancer Ther; 9(2); 319-26. ©2010 AACR.

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“…MDCK cells and Caco-2 cells have been reported to share many common epithelial cell characteristics (Putnam et al, 2002). A good correlation between the permeation of passively absorbed drugs across Caco-2 cells and MDCK cells suggests that MDCK model may be useful in place of Caco-2 cells as a monolayer model for intestinal mucosa (Irvine et al, 1999). In the late 1990s, a MDCKII-MDR1 cell line was generated by transfecting human mdr1 gene into MDCK cells.…”

Section: Introductionmentioning

confidence: 99%

Functional characterization of peptide transporters in MDCKII–MDR1 cell line as a model for oral absorption studies

Agarwal

Jain

Pal

et al. 2007

International Journal of Pharmaceutics

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MDCKII-MDR1 cell line has been extensively selected as a model to study P-gp-mediated drug efflux. Recently, investigators have employed this cell line for studying influx of peptide prodrug derivatives of parent compounds which are P-gp substrates. Therefore, the objective of this study is to functionally characterize the peptide mediated uptake and transport of [ 3 H] Glycylsarcosine ([ 3 H] Gly-Sar), a model peptide substrate across MDCKII-MDR1 cells. [ 3 H] Gly-Sar uptake from apical (AP) and basolateral (BL) membranes was found to be time dependent and saturable. MichaelisMenten (Km) constants of [ 3 H] Gly-Sar uptake across the AP and BL directions in MDCKII-MDR1 cell line were found to be 457 ± 37 μM and 464 ± 85 μM respectively. Vmax values in AP and BL directions for the peptide transporters in MDCKII-MDR1 cell line were calculated to be 0.035 ± 0.001 and 0.35 ± 0.034 pmol/min/mg protein respectively. Uptake of [ 3 H] Gly-Sar was significantly inhibited in the presence of aminocephalosporins and ACE-Inhibitors, known substrates for peptide transporters in both the AP and BL directions. Permeability of [ 3 H] Gly-Sar in the BL direction was maximal at pH 4 as compared to pH 5, 6 and 7.4 whereas such permeability in the AP direction was optimal at pH 7.4. Transepithelial transport of [ 3 H] Gly-Sar in the AP-BL direction was significantly lower than from BL-AP direction at all observed pHs. No statistical difference was observed in the transepithelial permeability of [ 3 H] Gly-Sar across both AP and BL directions over 4-10 days of growth period. The present study indicates that peptide transporters are effectively involved in the bidirectional transport of Gly-Sar across MDCKII-MDR1 cell line; the BL peptide transporter can transport Gly-Sar at a greater rate as compared to the AP peptide transporter. Results from these studies suggest the application of MDCKII-MDR1 cell line as a rapid effective tool to study peptide mediated influx of compounds that may be substrates for both P-gp and peptide transporters.

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MDCK (Madin-Darby Canine Kidney) Cells: A Tool for Membrane Permeability Screening

Cited by 834 publications

References 33 publications

Key to Opening Kidney for In Vitro–In Vivo Extrapolation Entrance in Health and Disease: Part I: In Vitro Systems and Physiological Data

Key to Opening Kidney for In Vitro–In Vivo Extrapolation Entrance in Health and Disease: Part I: In Vitro Systems and Physiological Data

Breast Cancer Resistance Protein and P-glycoprotein Limit Sorafenib Brain Accumulation

Functional characterization of peptide transporters in MDCKII–MDR1 cell line as a model for oral absorption studies

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