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In vitro hepatocyte uptake-based estimation of tissue partition coefficients of basic compounds for PBPK modeling
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DOI：10.1016/j.xphs.2026.104365.png)
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Abstract
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Accurate prediction of tissue-to-plasma partition coefficients (Kp,tissue) is critical for physiologically based pharmacokinetic (PBPK) modeling, particularly for basic compounds (pKa > 7) that display complex distribution driven by lysosomal sequestration and acidic phospholipid binding. We developed a novel in vitro method to estimate the hepatocyte partitioning coefficient (Kp,hep) using isolated, metabolically inactivated rat hepatocytes. For selected basic compounds, in vitro Kp,hep correlated strongly with in vivo liver partitioning (R² = 0.97), supporting its utility as a surrogate for hepatic distribution. Two strategies were then evaluated to extrapolate this information to other tissues. A scaling-factor approach based on the Poulin and Theil tissue composition-based model applied a liver-derived scalar across 11 tissues, improving prediction accuracy, with 60% and 73% of Kp values within 2-fold and 3-fold of observed data, respectively (AFE 0.70; AAFE 2.2). A second, regression-based approach adapted a prior muscle-derived model by estimating muscle Kp from hepatocyte Kp and extending predictions to additional tissues, yielding 63% and 83% of values within 2-fold and 3-fold, respectively (AFE 1.5; AAFE 1.8). These findings demonstrate that hepatocyte-based partitioning provides a practical, mechanistically relevant, and scalable method for predicting tissue distribution of basic compounds in PBPK modeling.
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