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AIM: The study investigates the potential interaction of the herbal medicinal product of Rhodiola rosea on the pharmacokinetics of losartan and its active metabolite EXP3174 after concurrent oral administration to rabbits. MATERIALS AND METHODS: We conducted a randomized, single-dose, two-treatment, two-period, two-sequence, cross-over pharmacokinetic study on 6 healthy female New Zealand rabbits, after concurrent oral administration of losartan (5 mg/kg) and the herbal medicinal product of R. rosea (50 mg/kg). Quantification of losartan and its main active metabolite EXP3174 was achieved using a validated HPCL/UV method. Pharmacokinetic and statistical analysis was performed using the EquivTest/PK software. OBSERVATIONS: Administration of the herbal medicinal product of R. rosea resulted in a statistically significant increase of the following pharmacokinetic parameters for losartan: the maximum plasma concentration (C(max)), the area under the curve (AUC) and the apparent total body clearance (CL/F). An almost 2-fold increase in the AUC of losartan was observed after concurrent administration of the herbal medicinal product of R. rosea. No statistically significant alteration was observed in the pharmacokinetic parameters of the active metabolite of losartan EXP3174. CONCLUSION: The data of this study suggest that R. rosea significantly alters the pharmacokinetic properties of losartan after concurrent oral administration to rabbits. A study in humans should be conducted to assess the clinical significance of a possible herb-drug interaction between the herbal medicinal products of R. rosea and drugs such as losartan, which are substrates of both CYPs and P-gp.

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European sea bass larvae were challenged by bath with Listonella anguillarum strain 332A, 2.5×10(7) CFUmL(-1) for 1h. Fish either received no treatment or oral treatment with Artemia franciscana (Kellog) nauplii enriched with oxolinic acid, or bath treatments with oxolinic acid. Medication commenced 1day following challenge and was performed on days 1, 3 and 5 post-challenge at a dosage of 20mgL(-1) for 2h for bath treatments, while two doses each of 750 nauplii per fish were administered daily for five consecutive days in oral treatments. Cumulative mortality reached 96% for the unmedicated challenged group, 32% in the group receiving bath treatments and 17% in the group receiving medicated nauplii. Pharmacokinetic parameters of oxolinic acid were calculated in sea bass larvae, for both treatments. Steady-state concentrations of oxolinic acid of 48.0 and 75.2µgg(-1) were achieved for bath treatment and oral treatment, respectively, while the elimination half-life was calculated to be 25.1h for bath treatment and 21.7h for oral treatment.

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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 (40 masculineC, 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.

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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.

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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.

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OBJECTIVE: To compare the relative bioavailability and bioequivalence of 2 enalapril tablet formulations in healthy volunteers under fasting conditions. METHODS: An open-label, single-dose, randomized, two-period, crossover trial with a 1-week washout period in 24 healthy volunteers. The 2 enalapril 20 mg tablet formulations used were Antiprex (Elpen, Greece) as test and Renitec (Vianex, Greece) as reference preparation. Serial blood samples were collected at 19 points for 36 h. Plasma samples were analyzed for enalaprilat, the pharmacologically active metabolite of enalapril, by a validated GC/MS assay. Pharmacokinetic parameters, such as AUC(0-infinity), AUC(0-t), C(max) T(max), t1/2 and MRT were calculated from plasma concentrations for both formulations. Statistical comparisons (ANOVA and 90% confidence intervals) of AUC(0-infinity), AUC(0-t) and C(max) data were evaluated after logarithmic transformation, and differences of T(max) were tested non-parametrically. RESULTS: The parametric 90% confidence intervals of the geometric mean values of the test/reference ratios were 88.0 - 117.6% (point estimate: 101.8%) for AUC(0-infinity), 88.7 - 118.9% (point estimate: 102.7%) for AUC(0-t), and 91.0% - 123.4% (point estimate: 106.0%) for C(max) No statistically significant differences were found between the 2 preparations for T(max) t1/2 and MRT values. CONCLUSIONS: From the results of the present study, it is concluded that the test and reference tablet formulations of enalapril are bioequivalent for both the extent and the rate of absorption and therefore the 2 products can be considered to be interchangeable in clinical practice.

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A rapid, specific, precise and accurate HPLC method with electrochemical detection was developed and validated for the determination of clarithromycin in human plasma. After addition of the internal standard, the analytes were extracted from plasma under alkaline conditions with ethyl acetate:hexane 1:1. The inter-run precision of the method was less than 4.7%, the inter-run accuracy was better than 97.3% and the recovery of clarithromycin and roxithromycin (internal standard) were better than 82.5% and 86.2%, respectively. The method was found to be suitable for the quantitation of clarithromycin in bioequivalence and pharmacokinetic studies.

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Flutamide is a potent antiandrogen used for the treatment of prostatic cancer. Flutamide undergoes extensive first-pass metabolism to the pharmacologically active metabolite 2-hydroxyflutamide. A simple, sensitive, precise, accurate and specific HPLC method, using carbamazepine as the internal standard, for the determination of 2-hydroxyflutamide in human plasma was developed and validated. After addition of the internal standard, the analytes were isolated from human plasma by liquid-liquid extraction. The method was linear in the 25 to 1,000 ng/ml concentration range (r>0.999). Recovery for 2-hydroxyflutamide was greater than 91.4% and for internal standard was 93.6%. The limit of quantitation was 25 ng/ml. Inter-batch precision, expressed as the relative standard deviation (RSD), ranged from 4.3 to 7.9%, and accuracy was better than 93.9%. Analysis of 2-hydroxyflutamide concentrations in plasma samples from 16 healthy volunteers following oral administration of 250 mg of flutamide provided the following pharmacokinetic data (mean+/-SD): Cmax, 776 +/- 400 ng/ml; AUC(0-infinity), 5,368 +/- 2,689 ng h/ml; AUC(0-t) 5,005 +/- 2,605 ng h/ml; Tmax 2.6 +/- 1.6 h; elimination half-life, 5.2 +/- 2.0 h.

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OBJECTIVE: The purpose of this study was to evaluate the relative bioavailability and bioequivalence of a test and a reference sublingual tablet each containing 5 mg of isosorbide dinitrate in healthy volunteers. METHODS: The study was conducted as an open-label, randomized, single-dose, two-period crossover design in 20 healthy volunteers with a washout period of 7 days, under fasting conditions. Plasma concentrations of the major active metabolite isosorbide 5-mononitrate were quantified, using a validated capillary gas chromatographic assay, with electron-capture detection. The pharmacokinetic parameters used to assess the bioequivalence of the two preparations were AUC(0-infinity) and AUC(0-infinity) for the extent of absorption and Cmax and tmax for the rate of absorption. RESULTS: The calculated 90% confidence intervals of the geometric mean values of the test/reference ratios were 98.2% to 103.2% (point estimate; 100.7%) for AUC(0-infinity) 96.9% to 103.8% (point estimate; 100.3%) for AUC(0-infinity), and 87.9% to 98.2% (point estimate; 92.9%) for Cmax. No statistically significant difference was found for tmax and elimination half-life (t 1/2) values. CONCLUSION: From the results of the present study, it is concluded that the test and reference isosorbide dinitrate sublingual preparations are bioequivalent in both extent and rate of absorption and it can be assumed that they are therapeutically equivalent and exchangeable in clinical practice.

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OBJECTIVE: The objective of this study was to compare the relative bioavailability and bioequivalence of a test (Claromycin®, GA Pharmaceuticals) and a reference (Klaricid®, Abbott) tablet containing 500mg clarithromycin in healthy volunteers under fasting conditions. METHODS: This was a nonblinded, single-dose, randomised, two-period, crossover study in 16 healthy volunteers conducted under fasting conditions. Plasma samples were analysed for clarithromycin by a validated high performance liquid chromatography assay with electrochemical detection. RESULTS: One volunteer did not receive the reference tablet. The parametric 90% confidence intervals of the geometric mean values of the test/reference ratios analysed for 16 participants were 84.2 to 111.6% (point estimate 97.3%) for the area under the plasma concentration-time curve for time zero to infinity (AUC0-∞), 82.2 to 117.6% (point estimate 98.3%) for time zero to time t (AUC0-t), and 74.4 to 142.9% (point estimate 103.1%) for peak plasma concentration (Cmax). No statistically significant differences were found between the formulations for the time to reach Cmax (tmax) and elimination half-life values. When the results were analysed for 15 participants, the 90% confidence intervals were 84.1 to 111.9% for AUC0-∞, 82.8 to 119.1% for AUC0-t, and 74.1 to 143.6% for (Cmax) CONCLUSIONS: From the results of this study, it is concluded that the two tablet preparations of clarithromycin are bioequivalent in both the extent and the rate of absorption.

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OBJECTIVE: To assess the bioequivalence of two oral formulations containing 10 mg of nifedipine. The test preparation were Macorel tablets, the reference preparation were Adalat tablets. SUBJECTS, MATERIAL AND METHODS: The study was designed as a single-dose, three-period crossover randomized design to 18 non-smoker, healthy male volunteers under fasting conditions. Seventeen volunteers completed the study. Plasma samples were analyzed for nifedipine by HPLC after solid-phase extraction. The pharmacokinetic parameters used to assess the bioequivalence of the two formulations were AUC(0-infinite) and AUC(0-t) for the extent of absorption and Cmax and Tmax for the rate of absorption. Statistical comparisons of AUC(0-infinite) AUC(0-t), and Cmax data were evaluated after logarithmic transformation by two-way analysis of variance (ANOVA), and differences of Tmax were tested non-parametricaly. RESULTS: Point estimates (90% confidence intervals) of the test/reference ratios were 97.4% (87.6%-108.3%) for AUC(0-infinite) 97.0% (85.6%-110.1%) for AUC0-t, and 107.7% (89.1%-130.7%) for Cmax. No statistically significant difference was found for Tmax and elimination half-life values. CONCLUSION: Therefore, in accordance with the European Union bioequivalence requirements, the test and reference nifedipine preparations are bioequivalent for both the extent and the rate of absorption.

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The pharmacokinetic parameters of two oral formulations of 100 mg tablets of atenolol (CAS 29122-68-7; Azectol as test and another commercially available preparation as reference) were compared in an open-label, randomized, single oral dose, two-period cross-over design to 17 healthy volunteers under fasting conditions. Serial blood samples were collected prior to each administration and at 17 points within 36 h after dosing. Plasma concentrations of atenolol were measured by a validated HPLC assay with fluorometric detection. The parametric 90% confidence intervals of the geometric mean values of the test/reference ratios were 94.4% to 112.9% (point estimate: 103%) for AUC0-infinity, 93.7% to 112.8% (point estimate: 103%) for AUC0-36, and 88.3% to 112.1% (point estimate: 100%) for Cmax, within the acceptance criteria for bioequivalence (80%-125%). Tmax values were analyzed by the nonparametric Wilcoxon test and the difference was not statistically significant. Therefore, it is concluded that the test and reference atenolol formulations are bioequivalent for both the extent and the rate of absorption.

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OBJECTIVE: The interaction of multiple oral doses of cimetidine on the steady-state pharmacokinetics and pharmacodynamics of warfarin was investigated in six healthy male volunteers. METHODS: The subjects were given individually adjusted doses of warfarin to achieve therapeutic levels of prothrombin activity. The established daily maintenance oral dose of warfarin was kept stable throughout the trial and, on study days 8-14, each volunteer received a 800-mg daily dose of cimetidine. The degree of anticoagulant response produced by warfarin was quantified by the determination of both the prothrombin time and factor-VII clotting activity. RESULTS: Cimetidine co-administration had no significant effect on the pharmacokinetics of the more potent S-warfarin but significantly increased by 28% (P < 0.05) mean R-warfarin trough plasma concentrations and decreased by 23% (P < 0.05) mean R-warfarin apparent clearance. Both prothrombin time and factor-VII clotting activity displayed considerable inter-subject variability and were not significantly affected by concurrent cimetidine treatment. The reduction of apparent clearance of R-warfarin by cimetidine was found to be the effect of inhibition of the formation of warfarin metabolites as determined by apparent formation clearance values (+/-SD) of R-6-hydroxywarfarin (31.1+/-7.4 ml/h baseline; 18.5+/-4.5 ml/h at end of cimetidine treatment; P < 0.01), and R-7-hydroxywarfarin (6.9+/-1.3 ml/h baseline; 4.3+/-1.1 ml/h at end of cimetidine treatment; P < 0.01). CONCLUSION: Cimetidine stereoselectively affects the steady-state pharmacokinetics of warfarin by inhibiting the disposition of the less potent R-warfarin in humans. However, this interaction is likely to be of minimal clinical significance in most patients.

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We conducted an open-label pilot study of dextromethorphan (DM) in intractable partial epilepsy with the following objectives: a preliminary evaluation of the drug's safety and efficacy in the epileptic patient and a definition of a concentration range which can be safely achieved in future studies. Sixteen patients with drug-resistant, localization-related epilepsies entered the trial. After an 8-week baseline period, DM was added to the existing antiepileptic drugs at a dose of 40 and 50 mg every 6 h (160 and 200 mg/day). Each treatment period lasted 8 weeks. Seizure control improved after administration of DM, especially in the group of intermediate and slow metabolizers. Two patients, however, experienced increased seizure frequency and withdrew from the study. Adverse effects during DM administration were mild and transient. DM was well tolerated even in patients with high plasma levels of the drug (up to 15020 ng/dl). Our results indicate that DM is safe and effective in the treatment of comedicated patients with intractable partial epilepsies.

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Transdermal administration of propranolol can be used to avoid hepatic first-pass metabolism of the drug. The effect of polysorbate 80 concentration on the permeation of propranolol incorporated into micelles of polysorbate 80 in water, oil-in-water microemulsions of isopropyl myristate-polysorbate 80-sorbitol-water and oil-in-water emulsions of isopropyl myristate-polysorbate 80-sorbitan monooleate-water has been investigated by use of an artificial double-layer membrane, composed of a barrier foil and a lipid barrier, in Franz-type diffusion cells. Reversed-phase high-performance liquid chromatography, with celiprolol as internal standard, was used to determine the concentration of propranolol in the receptor compartment and a logarithmic equation was used to estimate the apparent permeability coefficient of propranolol from disperse systems. For each disperse system the apparent permeability coefficient of propranolol decreased with increasing polysorbate 80 concentration. Moreover, for a given polysorbate 80 concentration the apparent permeability coefficient of propranolol increased when the disperse system was changed from emulsion to microemulsion and then to solubilized system, because of the increasing interfacial area of total disperse phase. The results show that transdermal permeation of propranolol is greater when it is diffused from solubilized systems rather than from microemulsions or emulsions.

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The pharmacokinetics of cefixime, a third-generation broad-spectrum cephalosporin, were determined following administration of a 8 mg/kg single oral dose of cefixime suspension to six children with urinary tract infections, ages from 6 to 13 years and weights from 17 to 60 kg. Blood samples for determination of plasma cefixime concentrations were obtained for up to 12 hr and complete urine collections were obtained for urinary excretion of unchanged parent drug for up to 24 hr after administration. Plasma and urine concentrations of cefixime were determined using a reversed phase HPLC assay and pertinent pharmacokinetic parameters were estimated by model-independent standard methods. Mean peak plasma concentration was 4.04 micrograms/ml and was reached after 3.2 hr. The mean area under the plasma concentration-time curve was 33.07 micrograms.hr/ml and the mean elimination half-life was 3.91 hr. The mean apparent total clearance was 4.74 ml/min./kg and about 15% of the dose administered was recovered unchanged in urine. In conclusion, the estimated pharmacokinetic values of cefixime were comparable to those observed in healthy adult subjects based on equivalent mg/ kg doses. Plasma and urine concentrations of the drug were well above the reported minimal plasma and urinary concentrations for most common urinary tract pathogens for up to 12 and 24 hr after administration, respectively.

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The present report describes the pharmacokinetic characteristics of dextromethorphan (DM) and its main active metabolite dextrorphan (DX) in a group of epileptic patients receiving comedication. Patients were sequentially dosed with DM 40 mg/6 h (8 weeks) and 50 mg/6 h (8 weeks) while concurrent antiepileptic drugs were kept stable. During baseline period, patients were phenotyped with regard to their drug metabolizing capacity. At the end of each treatment period, timed plasma DM and DX levels were determined post-dose by HPLC. Urine and cerebrospinal fluid f1p4) samples were also collected. The pharmacokinetic parameters of DM showed a wide intersubject variation. The genetic polymorphism of DM metabolism was identified as the possible cause of the observed variability. For both DM and DX mean values for Cmax and AUC increased in a linear fashion with dose, while the mean values of tmax and t 1/2 were not dependent on dose. The mean values of CL/F and Vss/F for DM were also dose-dependent. 3-Methoxymorphinan, an N-demethylated metabolite of DM was detected in plasma and CSF of some patients and warrants further investigation as to its possible CNS effects. In conclusion, DM given in doses up to 50 mg/6 h can produce plasma and brain concentrations similar to the in vitro antiepileptic levels, without causing significant adverse effects.

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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).

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Indomethacin and mefenamic acid are widely used clinically as non-steroidal anti-inflammatory agents. Both drugs have also been found effective to produce closure of patent ductus arteriosus in premature neonates. A simple, rapid, sensitive and reliable HPLC method is described for the determination of indomethacin and mefenamic acid in human plasma. As these drugs are not applied together, the compounds are alternately used as analyte and internal standard. Plasma was deproteinized with acetonitrile, the supernatant fraction was evaporated to dryness and the resulting residue was reconstituted in the mobile phase and injected into the HPLC system. The chromatographic separation was performed on a C18 column (250 x 4.6 mm I.D.) using 10 mM phosphoric acid-acetonitrile (40:60, v/v) as the mobile phase and both drugs were detected at 280 nm. The calibration graphs were linear with a correlation coefficient (r) of 0.999 or better from 0.1 to 10 micrograms/ml and the detection limits were 0.06 micrograms/ml for indomethacin and 0.08 micrograms/ml for mefenamic acid, for 50-microliters plasma samples. The method was not interfered with by other plasma components and has been found particularly useful for paediatric use. The within-day precision and accuracy of the method were evaluated for three concentrations in spiked plasma samples. The coefficients of variation were less than 5% and the accuracy was nearly 100% for both drugs.

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