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 C(max), T(max), AUC(0-t), AUC(0-infinity), CL/F, V/F, t(1/2), MRT, A(e), A(e)((0-24)), and R(max) 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 (C(max)) 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 AUC(0-infinity) 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.

Bioequivalence evaluation of 2 brands of cefuroxime axetil 250 mg tablets in healthy human volunteers.

OBJECTIVE: To assess the bioequivalence of 2 oral cefuroxime axetil (250 mg) tablets formulation. The reference preparation was Zinadol/Glaxo Wellcome, England, while the test preparation was cefuroxime axetil/Pharmathen, Athens, Greece. SUBJECTS, MATERIAL AND METHODS: The study was an open, randomized, 2-period, 2-sequence, 2-treatment crossover, involving 24 healthy male and female volunteers. All volunteers completed the study. Cefuroxime axetil plasma concentrations were measured utilizing a sensitive, reproducible and accurate HPLC method. Care was taken through the collection and analysis of the samples due to instability of cefuroxime axetil in light. Pharmacokinetic parameters used to assess bioequivalence were AUC(0-last), AUC(0-inf) for the extent of absorption and Cmax and tmax for the rate of absorption. Statistical evaluation of Cmax, AUC(0-last), and AUC(0-inf) was done using 2-way analysis of variance (ANOVA) after semilogarithmic transformation. Tmax values were tested using the distribution-free Hodges-Lehman interval. RESULTS: The parametric 90% confidence intervals for ratio T/R ranged from 98.91-111.65% (point estimate 105.09%) for AUC(0-last), 99.41-111.78% (point estimate 105.41%) for AUC(0-inf) and 87.61-102.89% (point estimate 94.95%) for Cmax, respectively. Based on the results of tmax, K(el) and t(1/2) there were no statistically significant differences. CONCLUSION: The 2 cefuroxime axetil preparations, examined in accordance with the European Union bioequivalence requirements, are equivalent with respect to rate and extent of absorption.

Comparative bioequivalence study of two isotretinoin soft gel capsule formulations in healthy male volunteers.

OBJECTIVE: To assess the bioequivalence of 2 oral isotretinoin (20 mg) soft gel capsule formulations. The reference preparation was Roaccutan/Roche while the test preparation was A-Cnotren/Pharmaten, Athens, Greece. SUBJECTS, MATERIAL AND METHODS: The study was an open, randomized, 2-period, 2-sequence, 2-treatment crossover, involving 38 healthy male volunteer subjects. All volunteers completed the study. Isotretinoin plasma concentrations were measured by a fully validated HPLC method. Special care was taken through the collection and analysis of the samples due to instability of isotretinoin to light and temperature. Pharmacokinetic parameters used to assess bioequivalence were AUC(0-last), AUC(0-infinity) for the extent of absorption and Cmax and Tmax for the rate of absorption. Statistical evaluation of Cmax, AUC(0-last), AUC(0-infinity) was done after semi-logarithmic transformation by 2-way analysis of variance (ANOVA). Tmax values were tested using the distribution-free Hodges-Lehman interval. RESULTS: The parametric 90% confidence intervals for ratio T/R ranged from 95.20-103.20% (point estimate 99.10%) for AUC(0-last), 94.57-102.30% (point estimate 98.36%) for AUC(0-infinity) and 94.81-102.90% (point estimate 98.77%) for Cmax, respectively. Based on the results of Tmax, k(el) and t(1/2), too, there were no statistically significant differences. CONCLUSION: As a result, the 2 isotretinoin preparations in accordance with the European Union bioequivalence requirements, are equivalent with respect to rate and extent of absorption.

Acyclovir serum concentrations following peroral administration of magnetic depot tablets and the influence of extracorporal magnets to control gastrointestinal transit.

In the present investigations peroral acyclovir depot tablets with internal magnets were developed. An extracorporal magnet was used to prolong the gastric residence times of the dosage forms and to influence the duration of absorption of acyclovir. The magnetic depot tablets contained 200 mg acyclovir. In a three-way cross-over in vivo study with five healthy male subjects, the plasma concentration-time profiles of acyclovir were determined. The acyclovir plasma concentrations following peroral administration of magnetic depot tablets in the presence and absence of an extracorporal magnet were determined. A commercially available immediate release preparation was used as a reference preparation. In the presence of an extracorporal magnet which was placed in the stomach region, the plasma concentrations of acyclovir were significantly higher after 7, 8, 10 and 12 h (P<0.05, U-test, Wilcoxon, Mann-Whitney). The mean area under the plasma concentration-time-curve (AUC0-24h), in the presence of the extracorporal magnet was 2802.7 ngh/ml. Without the extracorporal magnet a mean AUC0-24h of 1598.8 ngh/ml was achieved. Computer simulations were carried out to show the influence of the gastric residence time of acyclovir depot preparations on the plasma concentration-time profiles of acyclovir.

Pharmacokinetics of tolfenamic acid in pediatric patients after single oral dose.

The pharmacokinetics of tolfenamic acid, a non-steroidal anti-inflammatory drug, were determined following administration of a 1 mg/kg single oral dose of tolfenamic acid suspension to 6 feverish children. Their ages were from 2-14 years (mean 7.5 years) and their weights were from 12-50 kg (mean 29.2 kg). Tolfenamic acid produced a significant fall in temperature (about 2 degrees C) compared to the initial value before oral intake of the drug and was well tolerated without adverse effects. Blood samples for determination of tolfenamic acid concentrations in plasma were obtained at timed intervals for up to 8 h post-dose. Plasma concentrations of tolfenamic acid were determined using a reversed phase HPLC method and pertinent pharmacokinetic parameters were estimated by model-independent standard methods and were the following: the mean peak plasma concentration (Cmax +/- SEM) was 1.09 +/- 0.44 micrograms/ml (range, 0.65-1.63 micrograms/ml) and the mean time (tmax +/- SEM) to reach peak plasma concentration was 1.4 +/- 0.4 h (range, 0.5-3.0 h). The mean area under the plasma concentration-time curve (AUC0-->infinity +/- SEM) was 4.61 +/- 0.40 micrograms.h/ml (range, 2.74-5.98 micrograms.h/ml), the mean elimination half-life (t1/2 +/- SEM) was 2.82 +/- 0.21 h (range, 2.19-3.40 h) and the mean apparent total clearance (CL/F +/- SEM) was 3.83 +/- 0.41 ml/min/kg (range, 2.79-6.08 ml/min/kg).

Microencapsulation of potassium chloride with mastic.

The present investigation deals with the microencapsulation of potassium chloride with mastic. Spherical potassium chloride crystals with a mean particle diameter of approximately 450 microns were used. It could be shown that with a layer of mastic wall material thicker than 21 microns the release of potassium chloride in the in vitro test can be controlled for more than 6 h. The thickness of the wall material over the tested range of 21 to 33 microns has only a limited effect on the kinetics of release of potassium chloride. Increasing the thickness of the layer from 21 to 33 microns merely leads to a reduction of about another 10% in the amount of drug released in 6 h.

[Comparative in vitro studies of allopurinol in commercial preparations]. / Vergleichende in vitro-Untersuchungen von Allopurinol-Handelspräparaten.

Controls of content uniformity, disintegration and dissolution (in three different methods) were made in 5 commercial samples of allopurinol tablets. Two of the examined "normal tablets" were not acceptable. Our tests also resulted that U.S.P. XX "basket" dissolution method gives lower values of drug release than the two other methods (paddle).