Comparative steady state study with 2 fenofibrate 250 mg slow release capsules. An example of bioequivalence assessment with a highly variable drug.

Twenty healthy male volunteers were treated with 2 different oral preparations of fenofibrate according to a randomized 2-way crossover design. The test preparation was Fenofibrate 250 mg retard capsules, batch No. YXF 001, provided by MTT Medical and Technological Transfer GmbH, Unterhaching, Germany. The reference preparation was Lipanthyl 250 mg retard capsules, batch No. R9110071, manufactured by Fournier Pharma, Sulzbach, Germany. On 12 consecutive days divided in 2 periods the volunteers received 6 doses of the test and reference formulation, respectively. The daily dose of 1 capsule contained 250 mg of fenofibrate and was administered together with a standardized high calory breakfast. Blood samples were taken immediately prior to each administration and at 14 points after the last administration of each period. The concentration of the pharmacologically active compound, fenofibric acid, was determined by means of HPLC with UV detection. The calibration curve was linear in the range 0.1-20.0 micrograms/ml (r = 0.99997). A lower limit of quantification of 0.1 microgram/ml was established. The following mean values were obtained after administration of the test preparation: AUC tau 184.68 microgramsh/ml; Cmax 13.11 micrograms/ml; PTF: 125.0%. After administration of the reference formulation the following values were observed: AUC tau 175.91 microgramsh/ml, Cmax 12.27 micrograms/ml, PTF: 120.0%. AUC tau, Cmax and PTF were tested for bioequivalence parametrically after logarithmic transformation. The preparations were found to be bioequivalent.

Transsynovial kinetics of lonazolac and its hydroxy metabolite in synovitis patients.

OBJECTIVE: The study was designed to characterize the synovial distribution profiles and kinetics of the non-steroidal antiinflammatory agent, lonazolac, in patients with synovitis after multiple dosing with 300 mg tablets of lonazolac calcium salt. METHODS: Forty patients (36 male, 4 female) aged 21 to 50 years (mean: 38+/-9 years) undergoing arthroscopy of the knee joint for surgical reasons were given 7 total doses of drug administered as 300 mg oral tablets of lonazolac-calcium taken twice daily. Patients were assigned to one of 4 treatment groups (n = 10) in which arthroscopy was carried out 1, 2, 6, or 12 h after the seventh lonazolac dose. Samples of blood, synovial fluid, and synovial membrane were obtained during each operation and used to determine total concentrations of lonazolac and its main metabolite in plasma and synovial fluid by HPLC assay with UV detection. Free lonazolac concentrations in body fluids were determined after ultrafiltration by the same HPLC technique using a fluorescence detector. Tissue concentrations were assayed after additional steps using solvent and solid phase extractions. Total protein contents in plasma and synovial fluid were measured spectrophotometrically. RESULTS: Plasma drug levels were highest at 1 hour after dosing with mean peak concentrations of 1.8 mg/l total lonazolac, 1.2 mg/l total metabolite, and 9 microg/l free lonazolac. Profiles indicated a biphasic decline. Concentration vs. time profiles in synovial fluid were flattened compared to plasma profiles with mean peak values of 440 microg/l total lonazolac, 370 microg/l total metabolite, and 7 microg/l free lonazolac attained 2 hours after dosing. The mean unbound fraction of lonazolac was higher in synovial fluid (1.9%) compared to plasma (0.7%). Transsynovial partition coefficients increased continuously during a dosing interval from 0.16 to 3.15 for total lonazolac and from 0.56 to 5.05 for free lonazolac. Mean total protein contents for each group of patients ranged from 70 to 76 g/l for plasma and 32 to 42 g/l for synovial fluid. Total drug concentrations in synovial membrane were highest in tissues obtained 1 hour after dosing with mean values of approximately 1.0 microg/g dry weight. Tissue samples obtained at later times indicated that lonazolac profiles in tissue more closely resemble profiles obtained for plasma than for synovial fluid. Protein concentration ratios (synovial fluid : plasma) were between 0.45 and 0.58. Except for the absorption phase, transsynovial drug partition coefficients were always higher than the protein concentration ratios. CONCLUSIONS: Protein content is not an important factor for drug partition into inflamed joints after multiple dosing with lonazolac. Lonazolac distributes well into synovial fluid with therapeutically effective concentrations of unbound drug measured within 2 hours after dosing. Total lonazolac levels in synovial fluid exceed those measured in plasma at 6 to 12 hours after administration.

[The relative bioavailability of paracetamol following administration of solid and liquid oral preparations and rectal dosage forms]. / Untersuchungen der relativen Bioverfügbarkeit von Paracetamol nach Gabe von festen und flüssigen oralen Zubereitungen sowie rektalen Applikationsformen.

Determination of the Relative Bioavailability of Paracetamol Following Administration of Solid and Liquid Oral Preparations and Rectal Dosage Forms. The relative bioavailability of paracetamol from two solid and two liquid oral preparations and two rectal dosage forms, each containing 500 mg of the active ingredient, was investigated in 12 healthy male individuals. The plasma concentration-time curves of paracetamol following administration of the oral formulations were very similar; consequently there were only minor differences of the AUC0-12h (21.4, 21.9; 23.0, 22.8 micrograms.h/ml), cmax (8.8, 9.1; 10.0, 10.7 micrograms/ml), tmax (35, 25; 20, 19 min), and the terminal plasma elimination half-life t1/2 beta (2.95, 2.85; 2.86, 2.99 h) for the solid and the liquid test and reference preparations, respectively. The suppositories (test and reference formulation) differed from the oral dosage forms, but were comparable to each other with respect to AUC0-12h (18.2, 18.8 micrograms.h/ml), cmax (3.3, 3.5 micrograms/ml), tmax (1.6, 2.45 h), and t1/2 beta (3.55, 3.54 h). In all test preparations the 95% confidence limits for AUC0-12h completely were enclosed in the range of 80-120% relative bioavailability (independently of whether parametric or non-parametric statistical methods were applied); the limits for the oral formulations were quite narrow, thus indicating a highly consistent release of the active compound from the tablets as well as from the liquid dosage form. A comparison of the mean values of cmax by analysis of variance at the 80% probability level did not reveal any significant differences between the test and the corresponding reference formulations; based on non-parametric statistical methods, the 95% confidence limits for cmax were enclosed in the range of 70-130%.(ABSTRACT TRUNCATED AT 250 WORDS)

Liquid chromatography-mass spectrometry in metabolic research. I. Metabolites of benzbromarone in human plasma and urine.

Seven benzbromarone metabolites were identified in human plasma and urine by electron-impact mass spectrometry after semipreparative high-performance liquid chromatographic fractionation and/or by liquid chromatography-mass spectrometry using a thermospray interface. The major metabolite in plasma and urine was a hydroxybenzofuranoyl species; the 1-hydroxyethyl entity was identified as a minor metabolite. Five urinary metabolites occurred in trace amounts, all of them carrying OH and/or C = O groups in different positions. The hydroxybenzofuranoyl metabolite has often been mistaken for benzarone in previous studies.

Bioavailability investigation of two different oral formulations of methylprednisolone.

Two different oral methylprednisolone (CAS 83-43-2) formulations (Methylprednisolon-ratiopharm 8 mg tables as test preparation (T) and tablets of a reference preparation (R)) were investigated in 16 healthy volunteers in order to prove bioequivalence between these preparations. A single 8 mg oral dose was given according to a randomised two-way crossover design in the fasted state. Blood samples for determination of methylprednisolone plasma concentrations were collected at pre-defined time points up to 16 h following drug administration. A washout period of 3 days separated both treatment periods. Methylprednisolone plasma concentrations were determined by means of a validated HPLC method. Values of 342.53 ng.h/ml (test preparation) and 336.61 ng.h/ml (reference preparation) for the parameter AUC0-infinity demonstrate an nearly identical extent of drug absorption. Maximum concentrations (Cmax) of 66.58 ng/ml and 70.51 ng/ml were achieved for test and reference preparation. Time to reach maximum plasma concentration (tmax) was 2.2 h for both preparations. Cmax and AUC0-infinity-values were tested parametrically by the two one-sided t-test procedure. Bioequivalence was concluded if the 90% confidence intervals of the T/R-ratios were in the range of 80-125% for AUC0-infinity and 70-143% for Cmax. Based on the results obtained in this study, bioequivalence between Methylprednisolone ratiopharm and the reference preparation was demonstrated.

Bioequivalence evaluation of two flutamide preparations in healthy female subjects.

In the present study two different preparations containing 250 mg flutamide (3'-trifluoromethyl-4'-nitro-2-methyl-propionylanilide, CAS 13311-84-7) were compared in 20 female subjects. The trial was performed in a randomized two-way cross-over design. Each subject received one tablet with 250 mg flutamide in each period. The two treatment periods were separated by a wash-out phase of 7 days. Blood samples were obtained just before dosing and 18 times during the subsequent 36 h. The plasma concentrations of flutamide, 2-hydroxyflutamide and trifluoromethylnitroaniline were determined by HPLC with UV-detection. Due to the low plasma levels of the parent drug flutamide, the data of the pharmacologically active metabolite 2-hydroxyflutamide (CAS 52806-53-8) were used for bioequivalence assessment. The following mean values were obtained after administration of the test and reference preparation respectively: Flutamide: AUC0-36 = 95.82 ng.h/ml vs 93.33 ng.h/ml, Cmax = 44.78 ng/ml vs 38.73 ng/ml, tmax = 1.71 h vs 1.66 h, 2-hydroxyflutamide: AUC0-infinity = 6090.73 ng.h/ml vs 6068.83 ng. h/ml, Cmax = 772.74 ng/ml vs 779.84 ng/ml, tmax = 2.21 h vs 2.17 h, t1/2 = 8.21 h vs 8.32 h, trifluoromethylnitroaniline: AUC0-infinity = 1771.87 ng.h/ml vs 1701.44 ng.h/ml, Cmax = 173.36 ng/ml vs 171.32 ng/ml, tmax = 2.74 h vs 2.63 h, t1/2 = 10.75 h vs 9.83 h. The two preparations proved to be bioequivalent.

Acute and chronic anti-inflammatory properties of [2,2-dimethyl-6-(4- chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine-5-yl]-acetic acid.

The carrageenan-induced paw oedema in the rat was chosen as the experimental model for acute antiphlogistic activity. ED50 values of 3 mg/kg p.o. for indometacin and of 17 mg/kg p.o. for [2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2, 3-dihydro-1H-pyrrolizine-5-yl]-acetic acid (ML 3000) at calculated plasma levels (micrograms/ml) of approximately 5.0 and 20.0 were recorded for indometacin and ML 3000, respectively. The activity ratio of indometacin: ML 3000 is therefore about 1:6 with regard to the oral dose and about 1:4 with regard to the calculated plasma level. Indometacin is more potent than ML 3000 on the one hand, but on the other hand ML 3000 is better tolerated by the stomach in this experimental study: the ulcerogenic dose UD50 (indometacin) is 7 mg/kg p.o., whereas ML 3000 is tolerated well up to the highest tested dose of 100 mg/kg p.o. The adjuvant arthritis in the rat served as the model for chronic antiphlogistic activity. ML 3000 at doses of 20 mg/kg/d p.o. and higher, and indometacin at a dosage of 2 mg/kg/d p.o. produced a similar rate of reduction of the adjuvant-induced secondary lesions and paw swelling of the injected and uninjected paws, following prophylactic as well as therapeutic treatment with the compounds.