Gum kondagogu ( Cochlospermum gossypium) is a tree exudate gum that belongs to the family Bixaceae. Compositional analysis of the gum by HPLC and LC-MS revealed uronic acids to be the major component of the polymer ( approximately 26 mol %). Furthermore, analysis of the gum by GC-MS indicated the presence of sugars such as arabinose (2.52 mol %), mannose (8.30 mol %), alpha- d-glucose (2.48 mol %), beta- d-glucose (2.52 mol %), rhamnose (12.85 mol %), galactose (18.95 mol %), d-glucuronic acid (19.26 mol %), beta- d-galactouronic acid (13.22 mol %), and alpha- d-galacturonic acid (11.22 mol %). Gum kondagogu, being rich in rhamnose, galactose, and uronic acids, can be categorized on the basis of its sugar composition as a rhamnogalacturonan type of gum. The rheological measurements performed on the gum suggest that above 0.6% (w/v) it shows a Newtonian behavior and shear rate thinning behavior as a function of gum concentration. The viscoelastic behavior of gum kondagogu solutions (1 and 2%) in aqueous as well as in 100 mM NaCl solution exhibits a typical gel-like system. The G' (viscous modulus)/ G'' (elastic modulus) ratios of native gum kondagogu (1 and 2%) in aqueous solution were found to be 1.89 and 1.85 and those in 100 mM NaCl to be 1.54 and 2.2, respectively, suggesting a weak gel-like property of the polymer. Crossover values of G' and G'' were observed to be at frequencies of 0.432 Hz for 1% and 1.2 Hz for 2% for native gum in aqueous condition, indicating a predominantly liquid- to solid-like behavior, whereas crossover values of 2.1 Hz for 1% and 1.68 Hz for 2% gum in 100 mM NaCl solution suggest a larger elastic contribution.
A sensitive and specific liquid chromatography-tandem mass spectrometry method was developed and validated for the quantification of the plant natural product silvestrol in mice, using ansamitocin P-3 as the internal standard. The method was validated in plasma with a lower limit of quantification of 1 ng/mL, accuracy ranging from 87 to 114%, and precision (coefficient of variation) below 15%. The validated method was used to characterize pharmacokinetics in C57BL/6 mice and metabolism in mouse, human and rat plasma, and liver microsomes. Mice were dosed with silvestrol formulated in hydroxypropyl-β-cyclodextrin via intravenous, intraperitoneal, and oral routes followed by blood sampling up to 24 h. Intraperitoneal systemic availability was 100%, but oral administration resulted in only 1.7% bioavailability. Gradual degradation of silvestrol was observed in mouse and human plasma, with approximately 60% of the parent drug remaining after 6 h. In rat plasma, however, silvestrol was completely converted to silvestric acid (SA) within 10 min. Evaluation in microsomes provided further evidence that the main metabolite formed was SA, which subsequently showed no cytotoxic or cytostatic activity in a silvestrol-sensitive lymphoblastic cell line. The ability of the analytical assay to measure tissue levels of silvestrol was evaluated in liver, brain, kidney, and spleen. Results indicated the method was capable of accurately measuring tissue levels of silvestrol and suggested it has a relatively low distribution to brain. Together, these data suggest an overall favorable pharmacokinetic profile of silvestrol in mice and provide crucial information for its continued development toward potential clinical testing.
Curcumin and tetrahydrocurcumin (THC) have been found as potent DNMT1 inhibitors, but they suffer from low oral bioavailability and rapid metabolism in vivo. To circumvent these problems, two curcumin analogs: 1,7-bis(3,4-dimethoxyphenyl)-4,4-dimethyl-1,6-heptadiene-3,5-dione (TMC) and 1,7-bis(3,4-dimethoxyphenyl)-4-cyclohexyl-1,6-heptadiene-3,5-dione (DMCHC) have been synthesized to enhance their stability by blocking the two metabolic sites, the phenolic and C4 methylene moieties. Both compounds have shown inhibitory activity on M. SssI similar to that of curcumin and THC (Poster, M1114, AAPS, 2009. Preclinical pharmacokinetics has yet to be performed. In this paper, a simple liquid chromatography-tandem mass spectrometric method was developed for the determination of these four curcuminoids in cell medium and mouse plasma. The method showed linearity from 1 to 1000 ng/mL with the lower limit of quantification of 1 ng/ mL in cell medium, and 5 ng/mL in mouse plasma for all test curcuminoids. The within-day coefficients of variation were found to be below 15% and the accuracy was in the range of 85% to 115%. This method was subsequently used to evaluate their stability in these matrices and a pilot pharmacokinetics of curcumin, DMCHC and TMC in mice after an intraperitoneal (I.P.) cassette dosing of 10 mg/kg each. Curcuminoids degraded in two phases with terminal half lives of 186, 813, 724, and 2000 min for curcumin, THC, TMC, and DMCHC, respectively, in cell culture medium. In plasma, their respective half lives were 111, 232, 1202 and 3000 min. These data demonstrated that their stability is in the order curcumin
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