Physiologically based pharmacokinetic model of docetaxel and interspecies scaling: comparison of simple injection with folate receptor-targeting amphiphilic copolymer-modified liposomes

<p>1. To compare the disposition of docetaxel (DTX) in male/female rats after intravenous administration of simple injection and folate-poly(PEG-cyanoacrylate-co-cholesteryl cyanoacrylate)-modified liposomes utilising a physiologically based pharmacokinetic (PBPK) modelling method, and extrapolate this model to mice and humans by taking into account the interspecies differences in physiological- and chemical-specific parameters.</p> <p>2. Four structural models for single organs were evaluated, and the whole-body PBPK model included artery, vein, lung, brain, heart, spleen, liver, gastrointestinal tract, kidney, muscle and remainder compartment.</p> <p>3. Rats following modified liposomes administration were characterised by significant decrease in the partition coefficients for brain, spleen, liver and remainder compartment. The blood-to-plasma partition coefficient also decreased significantly, while a marked rise of partition coefficients for lung, kidney and muscle was revealed. Partition coefficient for heart was approximately 1.3-fold higher in females than males, while the decrease of intestinal clearance was revealed in females compared to males. The final model successfully characterised the time course of DTX in rats, mice and humans.</p> <p>4. This PBPK model is beneficial to the prediction of the effects of DTX in different species. It also represented a platform to encompass both formulation- and sex-related effects on DTX disposition and elimination in the future.</p

The PCA score plot and corresponding loading plot for the simulation data:

<p>(A) The score plot showing the separation between the Case group(X) and the Control group (o) (B) Loading plot for potential biomarker recognition. Metabolites 4, 6, 9, 11, and 12 are identified as potential biomarkers. Integers in red indicate biomarkers and integers in black indicate other markers.</p

LFDR plot for the metabolic profiles of the GF-treated and healthy control groups.

<p>(A) LFDR from 0 to 1 (B) LFDR form 0 to 0.20. The metabolites marked by blue X with retention time-m/z pair below the dash line are identified as the potential biomarkers. 0.05 (dash line) is treated as the threshold for potential biomarkers identification.</p

LFDR plot for simulation data of the Case group and the Control group.

<p>Integers in red indicate potential biomarkers and integers in black indicate other markers. 0.05 (dash line) is treated as the threshold for potential biomarkers identification. The integers below the dash line are identified as potential biomarkers.</p

Representative positive base peak intensity (BPI) chromatograms of urine samples at 336 h post-treatment:

<p>(A) GF-treated group (B) Healthy control group <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0067451#pone.0067451-Geng1" target="_blank">[19]</a>.</p

Biomarkers of hepatotoxicity induced by GF treatment.

*<p>Metabolite identified with database and commercially available references.</p>**<p>Metabolite identified with MS/MS fragment in the database and literature.</p

Experiment schedule.

<p>Experiment schedule.</p

Novel Antihypertensive Prodrug from Grape Seed Proanthocyanidin Extract via Acid-Mediated Depolymerization in the Presence of Captopril: Synthesis, Process Optimization, and Metabolism in Rats

Grape seed extract contains a high content of proanthocyanidins that can be depolymerized into C-4-substituted (epi)­catechin derivatives in the presence of nucleophiles. However, the biological and medicinal values of depolymerization products have been rarely investigated. Recently, we developed a novel depolymerization product (−)-epicatechin-4β-<i>S</i>-captopril methyl ester (ECC) derived from the reaction of grape seed proanthocyanidin extract with captopril in the presence of acidified methanol. A central composite design was employed to select the most appropriate depolymerization temperature and time to obtain the target product ECC with a high yield. A total of 16 metabolites of ECC in rat urine, feces, and plasma were identified using liquid chromatography quadrupole time-of-flight tandem mass spectrometry. The <i>in vivo</i> results suggested that ECC could release captopril methyl ester and epicatechin, followed by the generation of further metabolites captopril and epicatechin sulfate conjugates. Therefore, ECC may be used as a potential prodrug with synergistic or additive hypotensive effects

Total Lignans of <i>Schisandra chinensis</i> Ameliorates Aβ_1-42-Induced Neurodegeneration with Cognitive Impairment in Mice and Primary Mouse Neuronal Cells

<div><p>Lignan compounds extracted from <i>Schisandra chinensis</i> (Turcz.) Baill. have been reported to possess various biological activities, and have potential in the treatment of Alzheimer’s disease. This study was designed to investigate the effects of total lignans of <i>Schisandra chinensis</i> (TLS) on cognitive function and neurodegeneration in the model of AD induced by Aβ_1–42 <i>in vivo</i> and <i>in vitro</i>. It was found that intragastric infusion with TLS (50 and 200 mg/kg) to Aβ_1–42-induced mice significantly increased the number of avoidances in the shuttle-box test and swimming time in the target quadrant in the Morris water maze test. TLS at dose of 200 mg/kg significantly restored the activities of total antioxidant capacity (T-AOC), as well as the level of malondialdehyde (MDA) both in the hippocampus and cerebral cortex in mice. Results of histopathological examination indicated that TLS noticeably ameliorated the neurodegeneration in the hippocampus in mice. On the other hand, TLS (100 μM) could protect the Aβ_1–42-induced primary mouse neuronal cells by blocking the decrease of mitochondrial membrane potential (MMP), change the expressions of Bcl-2 (important regulator in the mitochondria apoptosis pathway). Moreover, TLS also decreased the activity of β-secretase 1 (BACE1), crucial protease contributes to the hydrolysis of amyloid precursor protein (APP), and inhibited the expression of JKN/p38, which involved in the MAPKs signaling pathways in both mice and primary mouse neuronal cells. In summary, TLS might protect against cognitive deficits and neurodegeneration by releasing the damage of oxidative stress, inhibiting the expression of BACE1 and the MAPKs inflammatory signaling pathways.</p></div

Effects of TLS on the expressions of JNK and p38 in Aβ_1-42-induced primary mouse neuronal cells.

<p>The expression of JNK (A), p38 (B). Values indicated mean ± S.E.M. and were analyzed by ANOVA followed by Tukey's multiple comparison test (<i>n</i> = 6). ^#<i>p</i> < 0.05, ^##<i>p</i> < 0.01 compared with the control group, ^<b>###</b><i>p</i> < 0.001 compared with the sham group; *<i>p</i> < 0.05, **<i>p</i> < 0.01 compared with the Aβ_1–42 group.</p