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To determine the contribution of the mdr1a gene product to digoxin pharmacokinetics, we constructed a physiologically based pharmacokinetic model for digoxin in mdr1a (-/-) and mdr1a (+/+) mice. After intravenous administration, total body clearance and tissue-to-plasma concentration ratios for muscle and heart were decreased in mdr1a (-/-) mice as compared with mdr1a (+/+) mice, and in particular, the digoxin concentration in the brain was 68-fold higher than that in mdr1a (+/+) mice at 12 h. On the other hand, mdr1a gene disruption did not change the contributions of renal and bile clearances to total clearance, the plasma protein binding, or the blood-to-plasma partition coefficient. Brain concentration-time profiles in mdr1a (+/+) and mdr1a (-/-) mice showed a different pattern from those in plasma and other tissues, indicating digoxin accumulation in the brain tissue. Because there was no difference in the uptake or release of digoxin by brain tissue slices from the two types of mice, we assumed the brain tissue compartment to consist of two parts (a well-stirred part with influx and efflux clearance and an accumulative part). Simulation with this model gave excellent agreement with observation when active efflux clearance across the blood-brain barrier was assumed to be zero in mdr1a (-/-) mice. The observations in other tissues in both types of mice were also well simulated.

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Environmentally benign lead-free ferroelectric (K0.5,Na0.5)(Mn0.005,Nb0.995)O3 (KNMN) thin film capacitors with a small concentration of a BiFeO3 (BF) dopant were prepared by a cost effective chemical solution deposition method for high energy density storage device applications. 6 mol. % BF-doped KNMN thin films showed very slim hysteresis loops with high maximum and near-zero remanent polarization values due to a phase transition from the orthorhombic structure to the pseudo-cubic structure. Increasing the electric field up to 2 MV/cm, the total energy storage density (Jtotal), the effective recoverable energy density (Jeff), and the energy conversion efficiency (η) of lead-free KNMN-BF thin film capacitors were 31.0 J/cm3, 28.0 J/cm3, and 90.3%, respectively. In addition, these thin film capacitors exhibited a fast discharge time of a few μs and a high temperature stability up to 200 °C, proving their strong potential for high energy density storage and conversion applications.

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