Permeability comparison between hepatocyte and low efflux MDCKII cell monolayer

Area of Science:

• Pharmacokinetics
• Drug Discovery
• Cell Biology

Background:

• Predicting oral absorption, brain penetration, and hepatic clearance relies on accurate passive permeability data.
• High-throughput (HT) measurement of passive permeability across hepatocyte membranes is challenging.
• Existing monolayer cell-based assays have limitations for HT hepatocyte permeability assessment.

Purpose of the Study:

• To evaluate the Madin-Darby canine kidney II-low efflux (MDCKII-LE) cell monolayer assay as a surrogate for predicting hepatocyte passive permeability.
• To assess the correlation between MDCKII-LE cell permeability and hepatocyte passive diffusion clearance.
• To investigate lipophilicity (Log D at pH 7.4) as an alternative surrogate for permeability prediction.

Main Methods:

• Utilized the HT MDCKII-LE cell monolayer permeability assay.
• Measured apparent passive permeability of compounds using MDCKII-LE cells.
• Correlated MDCKII-LE permeability with passive diffusion clearance in human and rat hepatocytes.
• Determined lipophilicity (Log D at pH 7.4) for tested compounds.

Main Results:

• Apparent passive permeability in MDCKII-LE cells showed a strong correlation with passive diffusion clearance of human and rat hepatocytes.
• Lipophilicity (Log D at pH 7.4) was well correlated with both MDCKII-LE and hepatocyte permeability for most compounds.
• The HT MDCKII-LE assay demonstrated potential as a reliable surrogate for hepatocyte passive permeability.

Conclusions:

• The HT MDCKII-LE cell assay can serve as a valuable surrogate for estimating hepatocyte passive permeability.
• Lipophilicity measurements offer a complementary approach for predicting compound permeability.
• These findings can aid in optimizing drug absorption, distribution, metabolism, and excretion (ADME) predictions.