Canine Mdr1 Knockout MDCK Cells Reliably Estimate Human Small Intestinal Permeability (P_eff) and Fraction Absorbed...

Area of Science:

• Pharmacokinetics and Drug Metabolism
• Cell Biology and In Vitro Models
• Drug Discovery and Development

Background:

• Human intestinal permeability significantly influences the oral absorption of active pharmaceutical ingredients (APIs).
• Accurate prediction of in vivo intestinal permeability is crucial for drug development and regulatory assessment.
• Madin-Darby Canine Kidney (MDCK) cell lines are widely used in vitro models for drug permeability studies.

Purpose of the Study:

• To evaluate an in-house canine Mdr1 knockout (cMdr1 KO) MDCK cell line for predicting human intestinal permeability.
• To establish correlations between in vitro apparent permeability (Papp) and human effective intestinal permeability (Peff).
• To assess the utility of this model for estimating oral fraction absorbed (fa) for new APIs.

Main Methods:

• Measurement of in vitro Papp for 16 reference compounds using the cMdr1 KO MDCK cell line under different pH conditions.
• Correlation analysis between measured Papp and established human Peff values.
• Estimation of Peff and fa for six test APIs using the established correlations.

Main Results:

• Strong correlations (R² > 0.8) were observed between in vitro Papp and human Peff across a range of permeabilities.
• Estimated Peff and fa values for test APIs showed good agreement with literature data and clinical pharmacokinetic studies.
• The cMdr1 KO MDCK model demonstrated particular utility for classifying highly permeable APIs.

Conclusions:

• The cMdr1 KO MDCK cell line is a valuable tool for predicting human intestinal permeability and drug absorption.
• This in vitro model supports accurate permeability classification, especially for highly permeable compounds.
• The findings support the broader application of this model in drug discovery, development, and regulatory submissions.