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The aim of the study was to determine the relative bioavailability and the pharmacokinetic parameters following administration of a slow-release formulation of isosorbide dinitrate (ISDN, Isdin) capsules (20, 40 and 60 mg). A gas chromatographic method was used to determine the plasma concentrations of ISDN and isosorbide-5-mononitrate (IS-5-MN). All of the required pharmacokinetic parameters were ascertained. The study was performed on 12 healthy volunteers in a steady-state crossover design. A comparison of the areas under the plasma concentration/time curves of the test preparations and the commercial preparations showed higher values for the test preparations in all of the investigations. However, these values were only statistically significant for the 40 and 60 mg formulations ISDN and the 60 mg formulation IS-5-MN.

For 4 different brands of indomethacin preparations the in vitro dissolution data as well as their relative bioavailabilities were determined. The in vitro tests were performed by the rotating basket method; the quantitative determinations of the serum-levels were determined by an gas chromatographic/mass spectrometric assay employing registration of the characteristic selected ion current profiles of the compound. Furthermore a special method for synthesis of the needed internal standard was also developed. The in-vivo-studies - with 15 volunteers in a 4 fold crossover-showed - in contrast to the worse in-vitro-dissolution of one preparation - bioequivalency of all four preparations. Our results clearly show that statements on in-vitro/in-vivo correlations have to be cautious.

The aim of this study was to determine the relative bioavailability of five oral allopurinol preparations and evaluation of the pharmacodynamic effect. Included were two slow-release formulations. The study was performed as complete five-way randomized steady-state cross-over trial in 10 healthy volunteers. Each day 300 mg of 1H-pyrazolo-(3,4-d) pyrimidin-4-ol (allopurinol) were orally administered for 7 days, followed by a wash-out phase of 14 days. The minimal serum levels of allopurinol and its major metabolite oxypurinol were determined by HPLC. In parallel the concentrations of uric acid in blood and in 24-h urine were measured. The two slow-release formulations had a significantly lower relative bioavailability compared to the normal formulations and, moreover, a slow-release effect could not be demonstrated. In all cases the clinical effect of the test preparations could be demonstrated, and a correlation between bioavailability and pharmacodynamic effect could be calculated. A correlation between published in vitro data and the present in vivo data could not be found.

For five different brands of acetylsalicylic acid (ASA) preparations the in vitro/in vivo data were determined and tested for comparability. The in vitro dissolution rates were determined by two different methods (Paddle, rotating basket) whereas the in vivo data were obtained from 15 volunteers in a 5-fold cross-over trial. The markedly worse in vitro dissolution (rotating basket) of one preparation is in contrast to the in vivo data which showed bioequivalency of all five preparations. It is doubled that in vitro measurements alone reveal sufficient informations for any predictions of the in vivo characteristics (e.g. bioavailability) of a preparation. It was possible to determine separately ASA and salicylic acid using a highly selective HPLC-method developed by us.

The relative bioavailabilities and pharmacokinetic profiles of 2 carbocisteine preparations (capsules, granulate) were evaluated in a single dose and a steady state study. 10 healthy volunteers took in a randomized, 2fold cross over design 750 mg 3-(carboxymethylthio)alanine (carbocisteine, Transbronchin) (1 portion of the granulate or 2 capsules) as a single dose or for 4 days 3 times a day (every 8 h) 1 portion of the granulate or 2 capsules, respectively. During the saturation phase the pre-dose serum levels in the morning were determined and on day 5 - after a last dosing the elimination kinetics were evaluated. The same time frame of blood withdrawals was used for the evaluation of serum kinetics after single dosing. The new developed gaschromatographic method for the rapid, sensitive and reliable quantitative determination of carbocisteine in serum saves not only a lot of time but also improves the detection limit and selectivity by a factor of approx. 10. The studies revealed bioequivalency of the carbocisteine granulate and capsule preparations. After multiple dosing, no cumulation of the carbocisteine serum levels occurred. A comparison of the AUCo-infinity and AUC tau (single/multiple dosing, respectively) showed linear pharmacokinetics without enzyme induction or saturation phenomena in man.