Prediction of the Time to Reach Equilibrium for Improved Estimation of the Unbound Fraction of Compounds in Equilibrium Dialysis Using kinetic Modeling.

Equilibrium dialysis (ED) is widely used in pharmacokinetics to determine the fraction of unbound (fu) compounds in plasma; however, the kinetics of drugs in the ED system with respect to their permeation across semi-permeable membranes has not been systemically studied. Here, the kinetics of the ED system, including the binding of drugs to plasma proteins, non-specific binding, and permeation across the membrane, was described to enable verification of the equilibrium, prediction of the time to reach equilibrium, and estimations of fu with data obtained during pre-equilibrium. Using data obtained during pre-equilibrium, the time to reach 90% equilibrium (t90%) and fu were estimated with reasonable accuracy. Notably, fu could be estimated reasonably well using one-time-point data for the calculation. Furthermore, the current modeling approach allowed concurrent estimations of fu and the decomposition rate of compounds that were metabolically unstable in the plasma. Reasonable metabolic rate constants were determined for cefadroxil and diltiazem, demonstrating the practicality of this method for determining kinetics related to fu characterization. Because the determination of fu of compounds with 'unfavorable' physicochemical properties is known to be experimentally challenging, the current method may be useful in determining the fu of compounds in vitro.

Generation of human iPSCs derived heart organoids structurally and functionally similar to heart.

Currently, due to the increasing demand for 3D culture, various organoids that mimic organs are being actively studied. Despite active reports, information on heart organoids (HOs), which are the first functional organs, is still insufficient. Parameters for reproducing hearts are: chamber formation, organization with cardiac cells, vascularization, and simulation of electrophysiological signals. In particular, since the heart reflects complex factors, it is necessary to develop HOs that can be simulated in depth. In this study, we have created self-organized HOs using human iPSCs, and validated mimicry of cardiac structures such as chamber and epicardium/myocardium and atrium/ventricle-similar areas. Furthermore, mechanical/electrophysiological features were verified through multiple analyzes after inhibition of ion channels. More importantly, the HOs function, due to the cardiovascular characteristics of HOs, was maintained through vascularization after in vivo transplantation. In conclusion, this study has the advantage of being able to easily and closely recapitulate morphological/functional aspects of the heart.