Evaluation of Fraction Unbound Across 7 Tissues of 5 Species

Abstract

Binding to various tissues and species is frequently assessed in drug discovery and development to support safety and efficacy studies. To reduce time, cost, and labor requirements for binding experiments, we conducted a large comparison study to evaluate the correlation of fraction unbound (f u ) across 7 tissues of 5 species, including white adipose, brain, heart, kidney, liver, lung, and skeletal muscle of mouse, rat, dog, monkey, and human. The results showed that there were no significant species differences of f u for tissue binding, and a single-species (e.g., rat) tissue f u can be used as a surrogate for binding in other species. Cross-tissue comparison indicated that brain, heart, liver, and muscle had quite similar f u values; rat liver binding can be used as a surrogate for binding of the other 3 tissues without any scaling factors. Binding to adipose, kidney, and lung can also be estimated with rat liver f u with scaling factors. This study suggests that a single tissue of a single species (e.g., rat liver) is a good predictor for f u of other tissues of various species with or without scaling factors. Molecular size, lipophilicity, pKa, and topological polar surface area are important physiochemical properties influencing tissue f u .

Physiologically‐Based Pharmacokinetic Modeling to Predict the Clinical Efficacy of the Coadministration of Lopinavir and Ritonavir against SARS‐CoV‐2

“…First, the f u,lung value used to predict K p,lung was determined using tissue homogenate and may not describe the intracellular drug binding accurately. 18 Second, due to limited availability of Chinese PK data, extensive validation of the Chinese model was not possible in the present study. Third, local and systemic inflammation, or mechanical interventions, such as intubation, may modify drug binding, distribution, or clearance in patients with COVID-19.…”

“…Our study has several limitations. First, the f u,lung value used to predict K p,lung was determined using tissue homogenate and may not describe the intracellular drug binding accurately 18 . Second, due to limited availability of Chinese PK data, extensive validation of the Chinese model was not possible in the present study.…”

“…For lopinavir, tissue K p values were predicted using the corrected Poulin and Thiel approach (method 1), except for human K p,lung , which was calculated from experimental values of unbound lopinavir fraction in lung (f u,lung ) and plasma (f u,p ). 18 The hepatic metabolism of lopinavir by CYP3A4 was accounted for using microsomal kinetic parameters, 2 whereas the maximal inactivation rate constant for MBI of CYP3A4 by lopinavir was optimized according to Wagner et al 8 For ritonavir, extensive metabolic kinetic parameters from recombinant CYP enzymes were coupled with intersystem extrapolation factors and incorporated into the model to account for its hepatic metabolism. 19,20 Subsequently, lopinavir (substrate) and ritonavir (inhibitor) models were linked.…”

“…In particular, a perfusion‐limited full PBPK distribution model was implemented to permit prediction of tissue concentrations. For lopinavir, tissue K p values were predicted using the corrected Poulin and Thiel approach (method 1), except for human K p,lung , which was calculated from experimental values of unbound lopinavir fraction in lung (f u ,lung ) and plasma (f u ,p ) 18 . The hepatic metabolism of lopinavir by CYP3A4 was accounted for using microsomal kinetic parameters, 2 whereas the maximal inactivation rate constant for MBI of CYP3A4 by lopinavir was optimized according to Wagner et al 8 .…”

Scientific Opinion of the Scientific Panel on Plant Protection Products and their Residues (PPR Panel) on testing and interpretation of comparative in vitro metabolism studies

“…It is recommended to use the same solvent, cell media, plastic device across species when conducting the comparative in vitro metabolism studies to minimise interference of non‐specific binding, to enable a reliable estimation of tissue binding and intracellular free active item concentrations (Mateus et al, 2017 ; Barr et al, 2019 ; Ryu et al, 2020 ; Hsu et al, 2021 ).…”