Pharmacokinetics, Mass Balance, and Biotransformation of [C]tinengotinib, A Novel Multi-target Kinase Inhibitor, in Healthy Subjects.

Background And Objective: Tinengotinib, a novel multi-target small molecule kinase inhibitor, is currently undergoing phase II clinical trial in the USA and China. The purpose of this open-label study was to investigate the absorption, metabolism, and excretion of [C]tinengotinib following a single oral dose in healthy subjects.

Methods: Six healthy male subjects received a single oral dose of [C]tinengotinib capsules at 10 mg/100 µCi, and blood, urine, and feces samples were collected.

In vitro and in vivo pharmacokinetics, disposition, and drug-drug interaction potential of tinengotinib (TT-00420), a promising investigational drug for treatment of cholangiocarcinoma and other solid tumors.

Early-stage clinical evaluation of tinengotinib (TT-00420) demonstrated encouraging preliminary efficacies in multiple types of refractory cancers, including fibroblast growth factor receptors (FGFR) inhibitors relapsed cholangiocarcinoma (CCA), castrate-resistant prostate cancer (CRPC), and HR+/HER2- breast cancer and triple negative breast cancer (TNBC). To further evaluate drug-like properties of the drug candidate, it is imperative to understand its metabolism and pharmacokinetic properties. This manuscript presented the investigation results of in vitro permeability, plasma protein binding, metabolic stability, metabolite identification, and drug-drug interaction of tinengotinib.

STSC-SNN: Spatio-Temporal Synaptic Connection with temporal convolution and attention for spiking neural networks.

Spiking neural networks (SNNs), as one of the algorithmic models in neuromorphic computing, have gained a great deal of research attention owing to temporal information processing capability, low power consumption, and high biological plausibility. The potential to efficiently extract spatio-temporal features makes it suitable for processing event streams. However, existing synaptic structures in SNNs are almost full-connections or spatial 2D convolution, neither of which can extract temporal dependencies adequately.

The metabolism and excretion of the dipeptidyl peptidase 4 inhibitor [C] cetagliptin in healthy volunteers.

The metabolism and excretion of cetagliptin were investigated in healthy male subjects after a single oral dose of 100mg/50μCi [C] cetagliptin.The mean concentration-time profile of cetagliptin was similar to that of total radioactivity in plasma after oral administration of [C] cetagliptin in healthy male subjects. Cetagliptin was rapidly absorbed after oral administration.

Mass balance, pharmacokinetics and pharmacodynamics of intravenous HSK3486, a novel anaesthetic, administered to healthy subjects.

Aims: This trial (NCT03751956) investigated the mass balance, pharmacokinetics and pharmacodynamics of HSK3486, a novel anaesthetic, in healthy subjects.

Methods: A single dose of 0.4 mg/kg [ C]HSK3486 was administered to six healthy subjects.

Absorption, Metabolism and Excretion of Surufatinib in Rats and Humans.

Background: Surufatinib is a potent small-molecule tyrosine kinase inhibitor and exhibited significant efficacy in the treatment of neuroendocrine tumors in clinical trials.

Objective: The absorption, metabolism and excretion of surufatinib were investigated in rats and human volunteers following a single oral dose of [14C] surufatinib.

Methods: The radioactivity was measured in plasma, urine, feces and bile by liquid scintillation counting, and the metabolites were characterized by liquid chromatography coupled to mass spectrometry.

Facile Synthesis, Magnetic and Electric Characterization of Mixed Valence LaKAMnTiO (A = Sr and Ba) Perovskites.

A new series of mixed valence perovskites, LaKAMnTiO (A = Sr and Ba) nanocubes, have been synthesized by a mild hydrothermal route. From powder X-ray diffraction (XRD) analysis, the crystal structure of LaKAMnTiO was solved as the orthorhombic symmetry (space group Pbnm) with a random A-site or B-site arrangement. The phase purity of the products was confirmed by ICP, SEM, and EDS analyses, and the oxidation states of the B-site metal atoms were determined to be +4 for Ti and +3/+4 for Mn from XPS results.

Pharmacokinetics, Metabolism and Disposition of [14C]XQ-1H After Intravenous Administration to Male Rats.

Objective: This study describes the in vivo pharmacokinetics and metabolism of [14C]labeled XQ-1H in male rats.

Methods: XQ-1H is a methanesulfonate of XQ, 10-O-(N,N-dimethylaminoethyl)-ginkgolide B, a derivative of ginkgolide B (GB) with enhanced water solubility. Since it is very difficult to synthesize radiolabeled GB, the results obtained in this study may provide helpful insight to further ADME investigation of GB and its analogue compounds.

3D Printable Graphene Composite.

In human being's history, both the Iron Age and Silicon Age thrived after a matured massive processing technology was developed. Graphene is the most recent superior material which could potentially initialize another new material Age. However, while being exploited to its full extent, conventional processing methods fail to provide a link to today's personalization tide.

4β-Hydroxycholesterol as an endogenous biomarker of CYP3A activity in cynomolgus monkeys.

It has been proposed that in humans 4β-hydroxycholesterol is formed mainly by CYP3A-catalyzed metabolism of cholesterol and thus may serve as an endogenous marker for CYP3A activity. The cynomolgus monkey is widely used as one of the nonrodent preclinical safety species in pharmaceutical research. In the current study, the potential application of 4β-hydroxycholesterol as an endogenous biomarker of CYP3A in response to drug treatment was evaluated in cynomolgus monkeys.

Disposition, metabolism and mass balance of [(14)C]apremilast following oral administration.

Apremilast is a novel, orally available small molecule that specifically inhibits PDE4 and thus modulates multiple pro- and anti-inflammatory mediators, and is currently under clinical development for the treatment of psoriasis and psoriatic arthritis. The pharmacokinetics and disposition of [(14)C]apremilast was investigated following a single oral dose (20 mg, 100 μCi) to healthy male subjects. Approximately 58% of the radioactive dose was excreted in urine, while faeces contained 39%.

Comparative metabolism of 14C-labeled apixaban in mice, rats, rabbits, dogs, and humans.

The metabolism and disposition of [(14)C]apixaban, a potent, reversible, and direct inhibitor of coagulation factor Xa, were investigated in mice, rats, rabbits, dogs, and humans after a single oral administration and in incubations with hepatocytes. In plasma, the parent compound was the major circulating component in mice, rats, dogs, and humans. O-Demethyl apixaban sulfate (M1) represented approximately 25% of the parent area under the time curve in human plasma.

Biotransformation of aesculin by human gut bacteria and identification of its metabolites in rat urine.

Aim: To observe the biotransformation process of a Chinese compound, aesculin, by human gut bacteria, and to identify its metabolites in rat urine.

Methods: Representative human gut bacteria were collected from 20 healthy volunteers, and then utilized in vitro to biotransform aesculin under anaerobic conditions. At 0, 2, 4, 8, 12, 16, 24, 48 and 72 h post-incubation, 10 mL of culture medium was collected.

Optimal modeling for phase I design of a two drug combination-results of a phase I study of cisplatin with 9-nitrocamptothecin.

Combination of platinum with topoisomerase-I inhibitors are synergistic. The objectives of this study were to determine MTD range and toxicity profile of combinations of oral 9-nitrocamptothecin (9NC) and intravenous cisplatin in patients with refractory solid tumors. Each course was 28 days starting on day 1 with cisplatin, and then 9NC daily for 5 days/week for three weeks.

The physicochemical properties and the in vivo AChE inhibition of two potential anti-Alzheimer agents, bis(12)-hupyridone and bis(7)-tacrine.

The lipophilicity and solubility profiles of bis(12)-hupyridone (B12H) and bis(7)-tacrine (B7T), two novel acetylcholinesterase inhibitors dimerized from huperzine A fragments and tacrine, respectively, were investigated over a broad pH range. Lipophilicity was assessed by both shake flask method with 1-octanol-water system and a reverse-phase HPLC system with methanol-water as mobile phase. The former method was used for determining the lipophilicities of the ionized forms (log D) of the dimers while the latter method was used for that of the neutral forms (log P).

Development of a high performance liquid chromatography-tandem mass method for determination of bis(7)-tacrine, a promising anti-Alzheimer's dimer, in rat blood.

An analytical method using on-line high performance liquid chromatography-tandem mass spectrometry with electrospray ionization was developed and applied for the quantification of bis(7)-tacrine (B7T) in rat blood. B7T and pimozide (internal standard, IS) were extracted in a single step from 100 microl of alkalized blood with ethyl acetate. Analytes were separated using an Extend C-18 column at 25 degrees C.

Comparative in vitro metabolism of 14C-ciclesonide in hepatocytes from the mouse, rat, rabbit, dog, and human.

The in vitro metabolism of ciclesonide, a novel inhaled nonhalogenated glucocorticoid for the treatment of asthma, was compared in cryopreserved hepatocytes from mice, rats, rabbits, dogs, and humans. Incubations of C-ciclesonide with individual hepatocyte suspensions revealed similar metabolite profiles in all 5 in vitro systems used. Ciclesonide was rapidly converted to its active metabolite, desisobutyryl-ciclesonide (des-CIC).

Ciclesonide disposition and metabolism: pharmacokinetics, metabolism, and excretion in the mouse, rat, rabbit, and dog.

The pharmacokinetics, metabolism, and excretion of ciclesonide, a novel and effective inhaled glucocorticoid for the treatment of asthma, were investigated after intravenous and oral administration of 14C-ciclesonide in the mouse, rat, rabbit, and dog. The pharmacokinetics of ciclesonide in all animal species were characterized by a low oral bioavailability (approximately 6% or less), a high clearance, and a large volume of distribution. The apparent terminal half-life of ciclesonide was short; the apparent terminal half-life of the active desisobutyryl-ciclesonide metabolite (des-CIC or M1) was longer and ranged from 2.

Reduction of nitriles to amines in positive ion electrospray ionization mass spectrometry.

Some compounds readily form [M+46]+ adduct ions during positive ion electrospray ionization mass spectrometry ((+)ESI-MS) analysis. These [M+46]+ ions were characterized as [M+CH3CH2NH2+H]+ by accurate mass determination. Ethylamine involved in the adduct was proposed to be the reduction product of acetonitrile and this was confirmed using deuterated acetonitrile.

Accurate mass filtering of ion chromatograms for metabolite identification using a unit mass resolution liquid chromatography/mass spectrometry system.

Acceleration of liquid chromatography/mass spectrometric (LC/MS) analysis for metabolite identification critically relies on effective data processing since the rate of data acquisition is much faster than the rate of data mining. The rapid and accurate identification of metabolite peaks from complex LC/MS data is a key component to speeding up the process. Current approaches routinely use selected ion chromatograms that can suffer severely from matrix effects.

Development of a bioanalytical liquid chromatography method for quantitation of 9-nitrocamptothecin in human plasma.

9-Nitrocamptothecin (9-NC) is an orally administered camptothecin (CPT) that is under evaluation in clinical trials. This compound is not fluorescent, which has hampered development of a sensitive high-performance liquid chromatographic (LC) assay for measurement of drug concentrations in clinical trials. We now report development of an assay that involves reduction of 9-NC to the fluorescent compound 9-aminocamptothecin (9-AC).