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Dicalcium phosphate anhydrous (DCPA, CaHPO4) is regarded as an orthopedic material due to its ability to match the generation of new bone to the rate of implant resorption without considering the material's mechanical stability. Additionally, magnesium (Mg) is widely recognized for its essential function in bone metabolism, especially during the initial phases of osteogenesis. Therefore, we explored the influences of Mg ions on DCPA powder, in biological responses, and on the enhancement of osteogenic properties. Mg-DCPA powders with varying substitution levels (0, 3, 5, and 7 mol%) were produced using the co-precipitation method. In the in vitro test, precipitates began to develop on the surface of the Mg-DCPA powders after 7 days. These results indicate that Mg ions in the DCPA powder could enhance the generation of a new apatite phase when subjected to physiological fluids on the surface of the powder. In addition, the osteogenic performance of the DCPA powder was improved by adding Mg ions. The most effective magnesium substitution content in the DCPA powder in order to improve its osteogenic potential was approximately 3 mol%. Consequently, this amount of magnesium in the DCPA powder could control the maintaining time in the implantation operation to produce a new apatite phase. [ABSTRACT FROM AUTHOR]

The purpose of this study is to investigate the difference of in vitro–in vivo correlation of α-amanitin from clearance perspectives as well as to explore the possibility of extra-hepatic metabolism of α-amanitin. First, a liquid chromatography-quadrupole-time-of-flight-mass spectrometric (LC-qTOF-MS) method for α-amanitin in rat plasma was developed and applied to evaluate the in vitro liver microsomal metabolic stability using rat and human liver microsomes and the pharmacokinetics of α-amanitin in rat. The predicted hepatic clearance of α-amanitin in rat liver microsomes was quite low (5.05 mL/min/kg), whereas its in vivo clearance in rat (14.0 mL/min/kg) was close to the borderline between low and moderate clearance. To find out the difference between in vitro and in vivo metabolism, in vitro and in vivo metabolite identification was also conducted. No significant metabolites were identified from the in vivo rat plasma and the major circulating entity in rat plasma was α-amanitin itself. No reactive metabolites such as GSH-adducts were detected either. A glucuronide metabolite was newly identified from the in vitro liver microsomes samples with a trace level. A semi-mass balance study was also conducted to understand the in vivo elimination pathway of α-amanitin and it showed that most α-amanitin was mainly eliminated in urine as intact which implies some unknown transporters in kidney might play a role in the elimination of α-amanitin in rat in vivo. Further studies with transporters in the kidney would be warranted to figure out the in vivo clearance mechanism of α-amanitin. [ABSTRACT FROM AUTHOR]

Polyethylene glycol (PEG) was introduced into synthetic bilirubin 3α and a PEGylated bilirubin 3α nanoparticle (BX-001N, Brixelle®) was developed for the first time. An in vitro microsomal stability study, in vivo PK studies with intravenous bolus (IV) and subcutaneous injection (SC), and a semi-mass balance study of BX-001N were investigated to evaluate its pharmacokinetic (PK) properties in male Sprague-Dawley (SD) rats using developed liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-qTOF/MS). Following IV administration at 10 or 30 mg/kg, BX-001N showed very low clearance (0.33–0.67 mL/min/kg) with predominant distribution in the vascular system (Vd = 51.73–83.02 mL/kg). BX-001N was also very stable in vitro liver microsomal stability study. Following SC administration at 10 or 30 mg/kg, the bioavailability of BX-001N in plasma at 10 mg/kg was around 43% and showed the less dose-proportionality at 30 mg/kg dose. BX-001N was mainly excreted via the urinary pathway (86.59–92.99% of total amount of parent drug in excreta; urine and faeces) not via the biliary one. [ABSTRACT FROM AUTHOR]

Most studies of Composite solid electrolytes (CSEs) are composed of a polymer matrix and ceramic fillers. Polymer matrix–based CSEs are prepared by dissolving a polymer and lithium (Li) salt in a toxic organic solvent; then, a ceramic filler is added, and the toxic solvent is evaporated. These electrolytes contain 80%–90% polymer; however, they still have low thermal and electrochemical stability and unsatisfactory suppression of Li dendrite growth compared to inorganic ceramic electrolytes (ICEs). Ceramic matrix–based CSEs have high electrochemical and thermal stability, and good interfacial contact with electrodes. In this study, ceramic matrix–based CSEs were fabricated at a low temperature using a nontoxic solvent via the cold sintering process (CSP). Then, polyvinylidene fluoride (PVDF) and lithium bis(trifluoromethanesulfonyl)imide (LiTFSI) were introduced on the LiTa 2 PO 8 (LTPO) particle interface. In addition, the effect of the ratio of LTPO–PVDF and PVDF–LiTFSI at the LTPO particle interface on the microstructure and electrochemical properties of composite pellets was investigated. LTPO–PVDF pellets exhibited a relative density of 82%–86%, and high adhesion between LTPO particles was observed due to the formation of PVDF–LiTFSI amorphous layer on the particle interface. The LTPO–PVDF composite pellets exhibited a high total ionic conductivity of 4.59 × 10−4 S/cm at room temperature (RT), negligible electronic conductivity of 3.89 × 10−8 S/cm, low activation energy of 0.259 eV, and sufficient electrochemical stability. Coin cells with LiMn 0.6 Fe 0.4 PO 4 (LMFP) cathode exhibited a high initial discharge capacity of ∼145 mAh/g and capacity retention of approximately 85% after 50 cycles at RT. These results prove that the CSP is an ideal fabrication method for CSEs than the conventional methods that use toxic solvents and that introducing an amorphous layer at the particle interface in ceramic matrix–based CSEs improves their ionic conductivity. [ABSTRACT FROM AUTHOR]

Most studies of Composite solid electrolytes (CSEs) are composed of a polymer matrix and ceramic fillers. Polymer matrix–based CSEs are prepared by dissolving a polymer and lithium (Li) salt in a toxic organic solvent; then, a ceramic filler is added, and the toxic solvent is evaporated. These electrolytes contain 80%–90% polymer; however, they still have low thermal and electrochemical stability and unsatisfactory suppression of Li dendrite growth compared to inorganic ceramic electrolytes (ICEs). Ceramic matrix–based CSEs have high electrochemical and thermal stability, and good interfacial contact with electrodes. In this study, ceramic matrix–based CSEs were fabricated at a low temperature using a nontoxic solvent via the cold sintering process (CSP). Then, polyvinylidene fluoride (PVDF) and lithium bis(trifluoromethanesulfonyl)imide (LiTFSI) were introduced on the LiTa 2 PO 8 (LTPO) particle interface. In addition, the effect of the ratio of LTPO–PVDF and PVDF–LiTFSI at the LTPO particle interface on the microstructure and electrochemical properties of composite pellets was investigated. LTPO–PVDF pellets exhibited a relative density of 82%–86%, and high adhesion between LTPO particles was observed due to the formation of PVDF–LiTFSI amorphous layer on the particle interface. The LTPO–PVDF composite pellets exhibited a high total ionic conductivity of 4.59 × 10−4 S/cm at room temperature (RT), negligible electronic conductivity of 3.89 × 10−8 S/cm, low activation energy of 0.259 eV, and sufficient electrochemical stability. Coin cells with LiMn 0.6 Fe 0.4 PO 4 (LMFP) cathode exhibited a high initial discharge capacity of ∼145 mAh/g and capacity retention of approximately 85% after 50 cycles at RT. These results prove that the CSP is an ideal fabrication method for CSEs than the conventional methods that use toxic solvents and that introducing an amorphous layer at the particle interface in ceramic matrix–based CSEs improves their ionic conductivity. [ABSTRACT FROM AUTHOR]

There have been many attempts in pharmaceutical industries and academia to improve the pharmacokinetic characteristics of anti-tumor small-molecule drugs by conjugating them with large molecules, such as monoclonal antibodies, called ADCs. In this context, albumin, one of the most abundant proteins in the blood, has also been proposed as a large molecule to be conjugated with anti-cancer small-molecule drugs. The half-life of albumin is 3 weeks in humans, and its distribution to tumors is higher than in normal tissues. However, few studies have been conducted for the in vivo prepared albumin-drug conjugates, possibly due to the lack of robust bioanalytical methods, which are critical for evaluating the ADME/PK properties of in vivo prepared albumin-drug conjugates. In this study, we developed a bioanalytical method of the albumin-conjugated MAC glucuronide phenol linked SN-38 ((2S,3S,4S,5R,6S)-6-(4-(((((((S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano [3′,4′:6,7] indolizino [1,2-b] quinolin-9-yl)oxy)methyl)(2 (methylsulfonyl)ethyl)carbamoyl)oxy)methyl)-2-(2-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-methylpropanamido)acetamido)phenoxy)-3,4,5-trihydroxytetra-hydro-2H-pyran-2-carboxylic acid) as a proof-of-concept. This method is based on immunoprecipitation using magnetic beads and the quantification of albumin-conjugated drug concentration using LC-qTOF/MS in mouse plasma. Finally, the developed method was applied to the in vivo intravenous (IV) mouse pharmacokinetic study of MAC glucuronide phenol-linked SN-38. [ABSTRACT FROM AUTHOR]

Daporinad (FK866) is one of the highly specific inhibitors of nicotinamide phosphoribosyl transferase (NAMPT) and known to have its unique mechanism of action that induces the tumor cell apoptosis. In this study, a simple and sensitive liquid chromatography–quadrupole-time-of-flight–mass spectrometric (LC-qTOF-MS) assay has been developed for the evaluation of drug metabolism and pharmacokinetics (DMPK) properties of Daporinad in mice. A simple protein precipitation method using acetonitrile (ACN) was used for the sample preparation and the pre-treated samples were separated by a C18 column. The calibration curve was evaluated in the range of 1.02~2220 ng/mL and the quadratic regression (weighted 1/concentration2) was used for the best fit of the curve with a correlation coefficient ≥ 0.99. The qualification run met the acceptance criteria of ±25% accuracy and precision values for QC samples. The dilution integrity was verified for 5, 10 and 30-fold dilution and the accuracy and precision of the dilution QC samples were also satisfactory within ±25% of the nominal values. The stability results indicated that Daporinad was stable for the following conditions: short-term (4 h), long-term (2 weeks), freeze/thaw (three cycles). This qualified method was successfully applied to intravenous (IV) pharmacokinetic (PK) studies of Daporinad in mice at doses of 5, 10 and 30 mg/kg. As a result, it showed a linear PK tendency in the dose range from 5 to 10 mg/kg, but a non-linear PK tendency in the dose of 30 mg/kg. In addition, in vitro and in vivo metabolite identification (Met ID) studies were conducted to understand the PK properties of Daporinad and the results showed that a total of 25 metabolites were identified as ten different types of metabolism in our experimental conditions. In conclusion, the LC-qTOF-MS assay was successfully developed for the quantification of Daporinad in mouse plasma as well as for its in vitro and in vivo metabolite identification. [ABSTRACT FROM AUTHOR]