Impact of Obesity and Bariatric Surgery on Metabolic Enzymes and P-Glycoprotein Activity Using the Geneva Cocktail Approach.

The inter-individual variability of CYP450s enzyme activity may be reduced by comparing the effects of bariatric surgery on CYP-mediated drug elimination in comparable patients before and after surgery. The current research will use a low-dose phenotyping cocktail to simultaneously evaluate the activities of six CYP isoforms and P-gp. The results showed that following weight reduction after surgery, the activity of all enzymes increased compared to the obese period, which was statistically significant in the case of CYP3A, CYP2B6, CYP2C9, and CYP1A2. Furthermore, the activity of P-gp after surgery decreased without reaching a statistical significance (p-value > 0.05). Obese individuals had decreased CYP3A and CYP2D6 activity compared with the control group, although only CYP3A was statistically important. In addition, there was a trend toward increased activity for CYP1A2, CYP2B6, CYP2C9, and CYP2C19 in obese patients compared to the control group, without reaching statistical insignificance (p-value ≥ 0.05). After six months (at least), all enzymes and the P-gp pump activity were significantly higher than the control group except for CYP2D6. Ultimately, a greater comprehension of phenoconversion can aid in altering the patient's treatment. Further studies are required to confirm the changes in the metabolic ratios of probes after bariatric surgery to demonstrate the findings' clinical application. As a result, the effects of inflammation-induced phenoconversion on medication metabolism may differ greatly across persons and drug CYP pathways. It is essential to apply these results to the clinic to recommend dose adjustments.

Evaluation of important human CYP450 isoforms and P-glycoprotein phenotype changes and genotype in type 2 diabetic patients, before and after intensifying treatment regimen using Geneva cocktail.

The present study evaluates the influence of type 2 diabetes (T2D) on important CYP450 (CYP) isoforms and P-glycoprotein (Pgp) transporter activities before and 3 months after an intensifying treatment regimen involving 40 patients. Results have been compared with 21 non-T2D healthy participants (the control group). CYPs and Pgp activities were assessed after administering the Geneva cocktail. The mean metabolic ratios (MR) for CYP2B6 (1.81 ± 0.93 versus 2.68 ± 0.87), CYP2C19 (0.420 ± 0.360 versus 0.687 ± 0.558) and CYP3A4/5 (0.487 ± 0.226 versus 0.633 ± 0.254) significantly decreased in T2D patients compared to the control group (p < 0.05). CYP2C9 (0.089 ± 0.037 versus 0.069 ± 0.017) activities slightly increased in diabetic patients, and no difference was observed regarding CYP1A2 (0.154 ± 0.085 versus 0.136 ± 0.065), CYP2D6 (1.17 ± 0.56 versus 1.24 ± 0.83), and Pgp activities in comparison to the control group. Three months after the intensifying treatment regimen, MRs of CYP2C9 (0.080 ± 0.030) and CYP3A4/5 (0.592 ± 0.268) improved significantly and were not statistically different compared to the control group (P > 0.05). Several covariables, such as inflammatory markers (IL-1ß and IL-6), genotypes, diabetes and demographic-related factors, were considered in the analyses. The results indicate that chronic inflammatory status associated with T2D modulates CYP450 activities in an isoform-specific manner.

Improved anti-inflammatory effects in rabbit eye model using biodegradable poly beta-amino ester nanoparticles of triamcinolone acetonide.

PURPOSE: Results of previous studies on the benefits of ocular drug delivery using polymeric mucoadhesive nanoparticles suggested longer presence and better penetration of nanoparticles, and, thus, increased effect and bioavailability of drugs entrapped in nanoparticles. In this study, a novel polymer, poly ß-amino ester, was used for the preparation of triamcinolone acetonide-loaded nanoparticles using a modified emulsification/solvent diffusion method. METHODS: Mucoadhesiveness studies, in vitro drug release, x-ray powder diffraction, differential scanning calorimetry, and scanning electron microscopy were used for physicochemical characterization of nanoparticles. Thirty-six hours after inducing uveitis by intravitreal injection of a lipopolysaccharide, sampling from the aqueous humor was done and inflammatory factors, such as cell, protein, nitric oxide, and prostaglandin E2, were compared. RESULTS: Nanoparticles with a mean size of 178 nm and drug loading of 5.3% were prepared and used for in vivo studies in rabbits with uveitis. Higher anti-inflammatory effect was observed for polymeric nanoparticles of triamcinolone acetonide compared with microparticles of prednisolone acetate and triamcinolone acetonide, and an equal effect compared with subconjunctival injection of triamcinolone acetonide in terms of inhibiting inflammation and inflammatory mediators. CONCLUSIONS: It can be concluded that polymeric nanoparticles of triamcinolone acetonide will provide as good an anti-inflammatory effect as the subconjunctival injection method and are better compared with other drug delivery systems.

Preparation and optimization of surface-treated methotrexate-loaded nanogels intended for brain delivery.

Nanogels loaded with methotrexate (MTX) were prepared via an ionic gelation process using chitosan and sodium tripolyphosphate (TPP). The preparation process was optimized by a systematic multi-objective-optimization approach in terms of the size, poly-dispersity index (PDI), loading efficiency (LE) and loading capacity (LC) of the resulting nanocarriers. A combination of the pH of the chitosan solution, the addition time of the TPP solution and temperature effects accounted for nearly 75% of the variation in nanogel size; the TPP initial concentration had a very significant effect on LE (p<0.0001). The final particle size (Z-average (r nm)), PDI, LE and LC corresponding to the optimal conditions were 59.27 nm, 0.34, 61.82% and 53.68%, respectively. As the ultimate goal, the surfaces of the MTX-loaded nanogels were modified by polysorbate 80 for the purpose of brain targeting. The cumulative in vitro release profiles of surfactant-coated and uncoated nanogels were almost identical and showed acceptable performance.

Optimization of the simultaneous determination of imatinib and its major metabolite, CGP74588, in human plasma by a rapid HPLC method using D-optimal experimental design.

A simple, rapid and specific HPLC method has been developed and validated for the simultaneous determination of imatinib, a tyrosine kinase inhibitor, and its major metabolite, CGP74588, in human plasma. The optimization of the HPLC procedure involved several variables, of which the influences of each was studied. After a series of preliminary-screening experiments, the composition of the mobile phase and the pH of the added buffer solution were set as the investigated variables, while the resolution between imatinib and CGP74588 peaks, the retention time and the imatinib peak width were chosen as the dependent variables. Applying D-optimal design, the optimal chromatographic conditions for the separation were defined. The method proved to show good agreement between the experimental data and predictive values throughout the studied parameter range. The optimum assay conditions were achieved with a Chromolith™ Performance RP-8e 100 mm × 4.6 mm column and a mixture of methanol/acetonitrile/triethylamine/diammonium hydrogen phosphate (pH 6.25, 0.048 mol L(-1)) (20:20:0.1:59.9, v/v/v/v) as the mobile phase at a flow rate of 2 mL min(-1) and detection wavelength of 261 nm. The run time was less than 5 min, which is much shorter than the previously optimized methods. The optimized method was validated according to FDA guidelines to confirm specificity, linearity, accuracy and precision.