Development of Physiologically Based Liver Distribution Model that Incorporates Intracellular Lipid Partitioning and Binding to Fatty Acid Binding Protein 1 (FABP1)

Steady-state volume of distribution <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mo>(</mml:mo> <mml:msub><mml:mrow><mml:mtext>V</mml:mtext></mml:mrow> <mml:mrow><mml:mtext>ss</mml:mtext></mml:mrow> </mml:msub> <mml:mo>)</mml:mo></mml:math> can be predicted using tissue-to-plasma partition coefficients <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mfenced> <mml:mrow> <mml:msub><mml:mrow><mml:mtext>K</mml:mtext></mml:mrow> <mml:mrow><mml:mtext>p</mml:mtext></mml:mrow> </mml:msub> </mml:mrow> </mml:mfenced> </mml:math> and tissue volumes. <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:msub><mml:mrow><mml:mtext>K</mml:mtext></mml:mrow> <mml:mrow><mml:mtext>p</mml:mtext></mml:mrow> </mml:msub> </mml:math> values are important components of physiologically based pharmacokinetic (PBPK) models, allowing for estimation of distribution kinetics and simulation of concentration-time profiles. Many <i>in silico</i> approaches have been developed to predict tissue <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:msub><mml:mrow><mml:mtext>K</mml:mtext></mml:mrow> <mml:mrow><mml:mtext>p</mml:mtext></mml:mrow> </mml:msub> </mml:math> values based on physicochemical processes that govern drug distribution. However, these methods frequently over- or under-predict tissue <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:msub><mml:mrow><mml:mtext>K</mml:mtext></mml:mrow> <mml:mrow><mml:mtext>p</mml:mtext></mml:mrow> </mml:msub> </mml:math> values, highlighting the need to consider additional mechanisms that can impact drug distribution kinetics. Many drugs have been shown to bind to rat and human fatty acid binding proteins (FABPs) <i>in vitro</i> but the impact of this binding to drug distribution has not been incorporated into <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:msub><mml:mrow><mml:mtext>K</mml:mtext></mml:mrow> <mml:mrow><mml:mtext>p</mml:mtext></mml:mrow> </mml:msub> </mml:math> predictions. We hypothesized that incorporating intracellular protein binding into tissue <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:msub><mml:mrow><mml:mtext>K</mml:mtext></mml:mrow> <mml:mrow><mml:mtext>p</mml:mtext></mml:mrow> </mml:msub> </mml:math> predictions will improve <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:msub><mml:mrow><mml:mtext>K</mml:mtext></mml:mrow> <mml:mrow><mml:mtext>p</mml:mtext></mml:mrow> </mml:msub> </mml:math> prediction accuracy. Using liver as a model organ, four physiologically based dynamic liver distribution models (LDMs) were developed to assess the role of distribution processes in <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:msub><mml:mrow><mml:mtext>K</mml:mtext></mml:mrow> <mml:mrow><mml:mtext>p</mml:mtext></mml:mrow> </mml:msub> </mml:math> predictions. The developed LDMs incorporated known distribution mechanisms and intracellular drug binding to liver FABP (FABP1). The liver <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:msub><mml:mrow><mml:mtext>K</mml:mtext></mml:mrow> <mml:mrow><mml:mtext>p</mml:mtext></mml:mrow> </mml:msub> </mml:math> values for drugs that bind to FABP1 were accurately predicted using the LDM that incorporates lipid partitioning, albumin distribution, and FABP1 binding but not using LDMs without FABP1 binding. Human FABP1 expression was quantified in 61 human livers and the interindividual variability in tissue FABP1 binding was incorporated into tissue <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:msub><mml:mrow><mml:mtext>K</mml:mtext></mml:mrow> <mml:mrow><mml:mtext>p</mml:mtext></mml:mrow> </mml:msub> </mml:math> predictions. These simulations showed that intracellular FABP1 binding can cause interindividual variability in <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:msub><mml:mrow><mml:mtext>K</mml:mtext></mml:mrow> <mml:mrow><mml:mtext>p</mml:mtext></mml:mrow> </mml:msub> </mml:math> values and result in concentration dependent tissue distribution.