•This is the first report to establish a reliable LC-MS/MS method for the quantification of TAK-438 P in biological samples.•The study showed that TAK-438 P were basically equivalent to TAK-438 F.•As the advantage of high water solubility, the injection of TAK-438 P will be promising in the clinical therapeutics.•TAK-438 P distributed rapidly and there was no long-term accumulation in most tissues.•The high accumulation in stomach revealed that stomach was likely to be the target organs of TAK-438 P.Vonoprazan Fumarate (TAK-438 F) is a new and effective drug approved in Japan in 2014 for treatment and prevention of acid-related diseases (ARDs), which exhibits many advantages compared with traditional proton-pump inhibitors (PPIs). However, the clinical applications of TAK0-438 F suffers limitation due to the lack of injection dosage form. Efforts to overcome this limitation lead to the systhesis of Vonoprazan pyroglutamate (TAK-438 P) for its high water solubility and more potent antisecretory effect. This was the first report to establish and validate a reliable and sensitive LC–MS/MS method for the quantification of TAK-438 P in rat plasma and tissues (heart, liver, spleen, liver, kidney, rain, stomach and small intestine). All the features of the developed method suggested it was within bioanalytical criteria recommended by regulatory authorities. Furthermore, the developed method was applied to the exploration of the bioequivalence between TAK-438 P and TAK-438 F, as well as the pharmacokinetics and tissue distribution of TAK-438 P. The results showed that there was no significant differences between TAK-438 P and TAK-438 F after oral administration of the same dose. Besides, TAK-438 P was rapidly absorbed and eliminated in rat plasma. And it was widely distributed and there was no long-term accumulation in most tissues. Notably, more than 2000 ng/mL was observed in stomach 12 h after oral administration. The high accumulation revealed that stomach was likely to be the target organs of TAK-438 P.

•Novel nonquaternary reactivators for nerve agent-inhibited AChE were constructed.•Some exhibited superior in vitro reactivation efficiency in comparison to 2-PAM.•Introduction of peripheral site ligand dramatically enhanced reactivation ability.•These conjugates may develop as efficient centrally activating reactivators.A new family of nonquaternary reactivators for nerve agent-inhibited human acetylcholinesterase (hAChE) were designed, synthesized and tested in this paper. It was found that salicylaldoximes were able to quickly cleave the P–S bond of organophosphate and avoid the reinhibition phenomenon in the reactivation process, but they lacked reactivating ability due to poor affinity for AChE. Based on a dual site binding strategy, different peripheral site ligands of AChE were introduced to achieve extra affinity. The in vitro reactivation experiments demonstrated that some of the yielding conjugates exhibited similar or even superior ability to reactivate sarin-, VX- or tabun-inhibited hAChE in comparison with the mono- and bis-pyridinium aldoximes currently used. Moreover, due to greatly improved lipophilicity, these nonquaternary conjugates hold promise for the development of efficient centrally activating reactivators.Based on a dual site binding strategy, the salicylaldoximes were conjugated to different peripheral site ligands through alkyl chains for construction of novel nonquaternary reactivators. Compared with the known quaternary pyridinium reactivators, some of the resulting compounds emerged as efficient and relatively broad-spectrum reactivators for nerve agent-inhibited human acetylcholinesterase.Download high-res image (162KB)Download full-size image

•A LC–MS/MS method was developed and validated for the determination of PA-824 in rat plasma and various tissues. The method has a good specificity, sensitivity and a short run time.•We investigated the pharmacokinetic of PA-824 in rat after a single oral administration.•We investigated the tissue distribution of PA-824 in rat after a single oral administration.A simple, sensitive and rapid LC–MS/MS method has been developed and validated for determination of PA-824 in rat biological samples using darunavir as internal standard. Chromatographic separation was achieved on an Inertsil®ODS3 C18 column (150 mm × 4.6 mm, 5 μm) using gradient elution of methanol-0.1% ammonia in water (90:10, v/v) with fast gradient elution at a flow rate of 0.6 mL/min and run time of 5 min. The mass spectrometer was run in positive electrospray ionization (ESI) mode using multiple reaction monitoring (MRM) to monitor the mass transitions. The optimized ion transition pairs for quantitation were m/z 360.1 → m/z 175.0 for PA-824, m/z 548.5 → m/z 504.2 for IS. The method was validated for accuracy, precision, linearity, range, selectivity, lower limit of quantification (LLOQ), recovery, matrix effect and robustness. All validation parameters met the acceptance criteria according to regulatory guidelines. The LLOQ was 0.05 μg/mL. The calibration curves showed a good linearity over the concentration range of 0.05–50 μg/mL. The calibration curves for all biological samples showed good linearity (r2 > 0.9978) over the concentration ranges tested. The recoveries obtained for PA-824 were ≥88.8%. The developed method was successfully applied to investigate the pharmacokinetics and tissue distribution of PA-824 in rats following oral administration. It was also the first study to investigate the tissue distribution of PA-824 in rats following oral administration.

A series of novel quinoline–docetaxel analogues (6a–6g, 13a–13g) were designed and synthesized by introducing bioactive quinoline scaffold to C2′-OH of docetaxel. The anticancer activities of these novel analogues were investigated against different human cancer cell lines including Hela, A549, A2780, MCF-7 and two resistant strains A2780-MDR and MCF-7-MDR. The data showed these analogues possessed similar to better cytotoxicity than docetaxel. Compound 6c was found to be the most potent one, and its IC50 value against MCF-7-MDR was 8.8 nM (IC50 of docetaxel was 180 nM). The work indicated that the introduction of quinolyl group in docetaxel could enhance cytotoxicity and reduce drug-resistance.

A simple and sensitive HPLC method has been developed and validated for the determination of tyrosol galactoside (TG) in rat plasma. After one-step protein precipitation with methanol, plasma samples were separated on an Ultimate AQ–C18 column (150 mm × 4.6 mm, 5 μm) using acetonitrile–water (7:93, v/v) as mobile phase at a flow rate of 1.2 mL/min. The ultraviolet detection wavelength was set at 275 nm. The lower limit of quantification was 1.140 μg/mL. The calibration curve was linear over a concentration range of 1.140–228.0 μg/mL. The assay accuracy and precision were within the range of 99.6–103.0 and 2.17–6.23%, respectively. The developed method was successfully applied to the pharmacokinetics study of TG in rats after intravenous and oral administration. The bioavailability of TG in rats is 27.9%.

3,5,4′-Tri-O-acetylresveratrol (TARES) synthesized by acetylating three hydroxyl groups of resveratrol (RES) is a prodrug of RES. The aim of this study was to investigate and compare the pharmacokinetics, tissue distribution and excretion of TARES and RES in rats following a single intragastric gavage (i.g.) administration. After RES is transformed into TARES, its pharmacokinetic properties are improved, such as the t1/2 has been prolonged and the AUC has been enhanced. And TARES follows linear plasma pharmacokinetics across the investigated dosage range in rats (77.5–310 mg/kg). The major distribution tissues of TARES or RES in rats were liver, spleen, heart and lung. TARES can increase the content of RES in lung significantly. There was no long-term accumulation of RES in rat tissues. Whether we administrated to rats of equimolar TARES or RES, total recoveries of RES in urine and feces within 36 h were low (0.99% or 0.07% in urine and 1.69% or 0.15% in feces).