Pharmacokinetics, distribution, and excretion of sodium oligomannate, a recently approved anti-Alzheimer's disease drug in China.

The National Medical Products Administration has authorized sodium oligomannate for treating mild-to-moderate Alzheimer's disease. In this study, an LC-MS/MS method was developed and validated to quantitate sodium oligomannate in different biomatrices. The plasma pharmacokinetics, tissue distribution, and excretion of sodium oligomannate in Sprague-Dawley rats and beagle dogs were systematically investigated. Despite its complicated structural composition, the absorption, distribution, metabolism, and excretion profiles of the oligosaccharides in sodium oligomannate of different sizes and terminal derivatives were indiscriminate. Sodium oligomannate mainly crossed the gastrointestinal epithelium through paracellular transport following oral administration, with very low oral bioavailability in rats (0.6%-1.6%) and dogs (4.5%-9.3%). Absorbed sodium oligomannate mainly resided in circulating body fluids in free form with minimal distribution into erythrocytes and major tissues. Sodium oligomannate could penetrate the blood-cerebrospinal fluid (CSF) barrier of rats, showing a constant area under the concentration-time curve ratio (CSF/plasma) of approximately 5%. The cumulative urinary excretion of sodium oligomannate was commensurate with its oral bioavailability, supporting that excretion was predominantly renal, whereas no obvious biliary secretion was observed following a single oral dose to bile duct-cannulated rats. Moreover, only 33.7% (male) and 26.3% (female) of the oral dose were recovered in the rat excreta within 96 h following a single oral administration, suggesting that the intestinal flora may have ingested a portion of unabsorbed sodium oligomannate as a nutrient.

Discovery of the First Potent Inhibitors of Mutant IDH1 That Lower Tumor 2-HG in Vivo.

Optimization of a series of R132H IDH1 inhibitors from a high throughput screen led to the first potent molecules that show robust tumor 2-HG inhibition in a xenograft model. Compound 35 shows good potency in the U87 R132H cell based assay and ∼90% tumor 2-HG inhibition in the corresponding mouse xenograft model following BID dosing. The magnitude and duration of tumor 2-HG inhibition correlates with free plasma concentration.

Quantitative LC/MS/MS method and pharmacokinetic studies of columbin, an anti-inflammation furanoditerpen isolated from Radix Tinosporae.

Columbin is an important component isolated from Radix Tinosporae. It has been demonstrated to possess many pharmacological activities, including anti-inflammation, antitumor and inhibition of enzyme activity in vivo. The purpose of the present study was to examine in vivo pharmacokinetics and bioavailability of columbin in rats using a high-performance liquid chromatography coupled with tandem mass spectrometry quantitative detection method. The columbin was extracted from rat plasma samples by methyl tert-butyl ether, evaporated and reconstituted in 100 microL methanol prior to analysis. The separation was performed using a Luna reversed-phase analytical column (5 microm, 100 x 2.0 mm) and an SB-C18 guard column (5 microm, 20 x 4.0 mm). The mobile phase was a mixture of methanol and water containing 25 mmoL/L NH(4)Ac (80:20, v/v). The method was validated within the concentration range of 5-5000 ng/mL, and the calibration curves were linear with correlation coefficients (r) >0.999. It was further applied to assess pharmacokinetics and oral bioavailability of columbin after i.v. and oral administration to rats. The oral bioavailability of columbin was only 3.18%, which indicated that columbin had poor absorption or underwent extensive first-pass metabolism.

Quantitative LC/MS/MS method and in vivo pharmacokinetic studies of vitexin rhamnoside, a bioactive constituent on cardiovascular system from hawthorn.

A simple and accurate liquid chromatography coupled with tandem mass spectrometry method was developed for determination and in vivo pharmacokinetic studies of vitexin rhamnoside in rat plasma. After protein precipitation using methanol, the analytes were separated by a Luna C(18) column with an isocratic elution and analyzed by mass spectrometry in multiple reaction monitoring mode using the respective negative ion at m/z 577.2-293.0 for vitexin rhamnoside and m/z 593.2-413.0 for internal standard (IS) vitexin glucoside. The method was validated systematically within the concentration range 5-5000 microg/L (R > 0.996) and the lower limit of quantitation was 5 microg/L. Acceptable precision and accuracy were acquired for concentrations over the standard curve range. It was further applied to assess pharmacokinetics and bioavailability of vitexin rhamnoside after intravenous and oral administration to rats. The oral bioavailability of vitexin rhamnoside was only 3.57%, which indicated that vitexin rhamnoside had poor absorption or underwent extensive first-pass metabolism. Practical utility of this new LC/MS/MS method was confirmed in pilot pharmacokinetic studies in rats following both intravenous and oral administration.