Feras Imad Kanaze

Pharmacokinetics of the citrus flavanone aglycones hesperetin and naringenin after single oral administration in human subjects

Background and objective:Hesperetin and naringenin, the aglycones of the flavanone glycosides hesperidin and naringin, occur naturally in citrus fruits. They exert interesting pharmacological properties such as antioxidant, anti-inflammatory, blood lipid and cholesterol lowering and are considered to contribute to health benefits in humans. However, no information is available on the pharmacokinetics of the citrus flavanones hesperetin and naringenin after their oral administration to humans as pure aglycones. Therefore, the objective of the present investigation was the evaluation of the pharmacokinetic parameters of hesperetin and naringenin in plasma and urine, after their single oral administration in humans in the form of solid dispersion capsules, and also to improve the absorption rate of flavanones by using aglycones rather than the naturally occurring glycosides.Design:Six healthy volunteers received orally 135 mg of each compound, hesperetin and naringenin, under fasting conditions. Blood samples were collected at 14 different time points over a 12 h period. Urine was collected over 24 h, in five sequential timed intervals. Plasma and urine hesperetin and naringenin concentrations, after enzymatic hydrolysis of their conjugated forms, were measured using validated high-pressure liquid chromatography methods. Pharmacokinetic parameters for hesperetin and naringenin, such as Cmax, Tmax, AUC0−t, AUC0−∞, CL/F, V/F, t1/2, MRT, Ae, Ae(0–24), and Rmax were calculated from their plasma or urine concentrations.Results:Pharmacokinetic analysis showed that both hesperetin and naringenin were rapidly absorbed and their concentrations in plasma observed 20 min after dosing and reached a peak in 4.0 and 3.5 h, respectively. The mean peak plasma concentration (Cmax) for hesperetin and naringenin were 825.78±410.63 ng/ml (2731.8±1358.4 nmol/l) and 2009.51±770.82 ng/ml (7386.6±2833.4 nmol/l), respectively and the mean AUC0−∞ values were 4846.20±1675.99 ng h/ml and 9424.52±2960.52 ng h/ml for hesperetin and naringenin, respectively. The elimination half-life for hesperetin was found to be 3.05±0.91 h and for naringenin 2.31±0.40 h, respectively. The mean values of the relative cumulative urinary excretion, as percentage of the administered dose, for hesperetin and naringenin, were found to be 3.26±0.44 and 5.81±0.81%, respectively.Conclusions:Oral administration of the flavanone aglycones, hesperetin and naringenin, lead to their rapid absorption as their conjugated forms. The cumulative urinary recovery data indicated low bioavailability for both flavanone aglycones, owing to extensive first-pass metabolism partly by cleavage of the C-ring by the enzymes of intestinal bacteria leading to degradation products such as phenolic acids.

Simultaneous reversed-phase high-performance liquid chromatographic method for the determination of diosmin, hesperidin and naringin in different citrus fruit juices and pharmaceutical formulations

Diosmin, hesperidin and naringin are flavonoid glycosides that occur naturally in citrus fruits. They exert a variety of pharmacological properties such as anti-inflammatory, antioxidant and free radical scavenging and antiulcer effects and also inhibit selected cytochrome P-450 enzymes resulting in drug interactions. A reversed-phase high-performance liquid chromatographic method has been developed for the simultaneous determination of diosmin, hesperidin and naringin in different citrus fruit juices and pharmaceutical preparations. Diosmin, hesperidin, naringin and the internal standard rhoifolin were separated using tetrahydrofuran/water/acetic acid (21:77:2, v/v/v) as the mobile phase at 34 degrees C, using a C8 reversed-phase column. The method was linear in the 0.25-20.0 microg/ml concentration range for all three flavonoid glycosides (r>0.999). The method has been successfully applied to the determination of all three flavonoid glycosides in several samples of different citrus fruit juices sold in Greece and for the determination of diosmin and hesperidin in pharmaceutical preparations.

Developing and optimizing a validated isocratic reversed-phase high-performance liquid chromatography separation of nimodipine and impurities in tablets using experimental design methodology.

In the present study an isocratic reversed-phase high-performance liquid chromatography was investigated for the separation of nimodipine and impurities (A, B and C) using statistical experimental design. Initially, a full factorial design was used in order to screen five independent factors: type of the organic modifier - methanol or acetonitrile - and concentration, column temperature, mobile phase flow rate and pH. Except pH, the rest examined factors were identified as significant, using ANOVA analysis. The optimum conditions of separation (optimum values of significant factors) determined with the aid of central composite design were: (1) mobile phase: acetonitrile/H(2)O (67.5/32.5, v/v), (2) column temperature 40 degrees C and (3) mobile phase flow rate 0.9 ml/min. The proposed method showed good prediction ability (observed-predicted correlation). The analysis was found to be linear, specific, precise, sensitive and accurate. The method was also studied for robustness and intermediate precision using experimental design methodology. Three commercially available nimodipine tablets were analyzed showing good % recovery and %RSD. No traceable amounts of impurities were found in all products.

Dissolution rate and stability study of flavanone aglycones, naringenin and hesperetin, by drug delivery systems based on polyvinylpyrrolidone (PVP) nanodispersions

Objective: To study the dissolution behavior, the release mechanism and the stability of nanodispersion system of aglycones with PVP. Methods: The nanodispersion system of polyvinylpyrrolidone (PVP)/naringenin–hesperetin was prepared using the solvent evaporation method. The chemical stability (compatibility) of naringenin and hesperetin in the prepared dispersions was studied under accelerated conditions for 3 months. The evaluation of physical stability was performed by X-ray diffraction analysis (XRD) and by comparing the dissolution profile before and after storage at high temperature and moisture (40ºC, RH 75%). Results: The dissolution rate of naringenin and hesperetin released was dramatically increased in the nanodispersion system of PVP/naringenin–hesperetin (80/20, w/w). The release mechanism of both flavanone aglycones was better described by the diffusion model (Higuchi model). Also it was found that the rate-limiting step that controlled the release of naringenin and hesperetin in the nanodispersion system was dissolution of the carrier (PVP). Conclusions: During accelerated degradation analysis, for 3 months at high temperature and moisture, PVP nanodispersion system showed enhanced chemical compatibility and physical stability. The physical evaluation (obtained from XRD analysis) of PVP/naringenin–hesperetin (80/20, w/w) in the selected storage conditions did not show any crystallization of flavanone aglycones in the PVP nanodispersion system or any change in their release profile.

Nanoencapsulation of nimodipine in novel biocompatible poly(propylene-co-butylene succinate) aliphatic copolyesters for sustained release

Biocompatible poly(propylene-co-butylene succinate) (PPBSu) copolyesters, containing up to 50 mol% butylene succinate units, were synthesized by the two-stage melt polycondensation method (esterification and polycondensation). The copolymers were fully characterized and biocompatibility studies were also performed. They were proved to be biocompatible and they were used as polymermatrices for the preparation of drug loaded nanoparticles. Nimodipine was selected as a model hydrophobic poorly water soluble drug. From the results obtained by dynamic light scattering (DLS) and scanning electron microscopy (SEM), drug loaded copolymer nanoparticles were found to exhibit a spherical shape and their mean diameter appeared in the range of 180-200 nm. Fourier Transformation-Infrared Spectroscopy (FTIR) spectra indicated that no chemical interaction between the drug and the matrix could be justified, while Wide-Angle X-Ray Diffraction (WAXD) patterns proved a low degree of crystallinity of Nimodipine in the nanoparticles. The release behavior of the model drug from nanoparticles was also investigated in order to identify modifications and find out any possible correlation between the chemical composition of the polymer matrix and the drug release rates.

Tailoring the Release Rates of Fluconazole Using Solid Dispersions in Polymer Blends

Formulations of the drug Fluconazole with different release characteristics were prepared by dispersing the active pharmaceutical ingredient (API) in various polymeric carriers, and especially in polymer blends. Fluconazole was tested as a model drug with low solubility in water. First solid dispersions in pure polymers were studied. Use of pure polyvinylpyrrolidone (PVP) as carrier even for high drug load (30 wt%) resulted in rapid release. The drug release rates decreased by increasing the API content. The dissolution rate enhancement was attributed to drug amorphization, particle size reduction, and possible improvement of the drug wetting characteristics. Hydroxypropyl methylcellulose (HPMC) gave solid dispersions, from which the release rates of the drug varied from immediate to sustaining. As the drug amount increased, the rates became higher. Similar behavior also was found when Chitosan was used as carrier, with much more controlled rates close to those for sustained release. These differences were mainly attributed to the limited solubility and swelling of HPMC and Chitosan in aquatic media. To study the effectiveness of polymer blends in adjusting the release rates of the drug, solid dispersions in PVP/HPMC and PVP/Chitosan miscible blends were studied. The release rates of Fluconazole were adequately adjusted by differentiating the weight ratio of the polymers in the blends. PVP/HPMC blends with high PVP content can be used for immediate release formulations but PVP/Chitosan blends are inappropriate for such formulations and can only be used for controlled release.

Frequency distribution of dextromethorphan O-demethylation in a Greek population

OBJECTIVE To determine the CYP2D6 phenotype in a Greek population by using dextromethorphan (DM) as a probe drug. METHODS DM (30 mg) was given orally to 102 unrelated Greek subjects and 8-hour urine samples were collected. Concentrations of DM and its metabolite dextrorphan (DX) were determined using a validated HPLC assay. Metabolic molar ratio (MR) of DM to free DX in log form was used as an in vivo index of metabolic status. RESULTS The frequency distribution histogram of MR was bimodal. An antimode of 0.25 for the mean log MR was determined using probit analysis. Seven of 102 subjects (6.9%) were poor metabolizers (PMs). CONCLUSION The PM frequency of CYP2D6 in Greek subjects was similar to other Caucasian populations.