Bioequivalence of allopurinol preparations: to be assessed by the parent drug or the active metabolite?

Allopurinol is converted almost completely into a single active metabolite, oxipurinol, which has the same therapeutic pattern but a much longer elimination half-life than the parent compound. Therefore both allopurinol and oxipurinol were evaluated in our bioequivalence study in healthy volunteers comparing two allopurinol brands. Bioequivalence determination was based on the 90% confidence intervals (CI) of the area under the plasma concentration time curve from time zero to infinity (AUC0-infinity), of the area from time zero to the last measurable plasma concentration (AUC0-t (last)), and Cmax. Because of the lack of compound-specific criteria we used conventional limits for the bioequivalence range. Under these conditions the brand chosen as test preparation was judged to be bioequivalent to the reference form with respect to the extent of bioavailability, AUC0-infinity, and AUC0-t (last) of the parent drug. The CI of Cmax of allopurinol slightly exceeded the upper limit of 130%, so that bioequivalence was not confirmed with regard to the rate of bioavailability of the parent compound. The CI values of both AUC and Cmax of the active metabolite were tighter than those of allopurinol. In addition, the CI values of Cmax of oxipurinol were smaller than those of the corresponding AUC. As a consequence the test drug can clearly be accepted as bioequivalent, based on metabolite data. Since the active metabolite is of greater therapeutic significance than the parent drug, assessment of the bioequivalence of allopurinol preparations needs to be based on oxipurinol rather than allopurinol.(ABSTRACT TRUNCATED AT 250 WORDS)

Bioavailability study of two different verapamil formulations.

Relative bioavailability and bioequivalence of two oral verapamil preparations were investigated (dosage 80 mg, film-coated tablets as reference, dragées as test formulation). The clinical study was performed in a 2-period-cross-over design with 16 male healthy volunteers (mean age 28.8 +/- 3 years). The active metabolite norverapamil was included in the investigation. To assess bioequivalence several pharmacokinetic characteristics (i.e. AUC(o-oo), Cmax, tmax) were taken into account. Shortest 90% confidence intervals were calculated based on parametric (ANOVA, ANOVAlog) and non-parametric (Wilcoxon, Mann-Whitney) statistical tests. A positive decision for bioequivalence was accepted if the confidence intervals did not exceed the limits of 80-120% for AUC and 70-130% for Cmax. A mean relative bioavailability of 127% for the test preparation was found. Thus, bioavailability of the dragées is marked higher than bioavailability of the film-coated tablets.

[Bioavailability and bioequivalence of organic nitrates. Isosorbide dinitrate--a study of sustained-release preparations]. / Bioverfügbarkeit und Bioäquivalenz von organischen Nitraten. Isosorbiddinitrat-Untersuchungen zu Fertigarzneimitteln mit retardierter Wirkstoff-Freisetzung.

Assessment of Bioavailability of Organic Nitrates/Comparative bioavailability study of sustained-release isosorbide dinitrate preparations. Relative bioavailabilities of isosorbide dinitrate (ISDN, CAS 87-33-2) and the metabolite isosorbide-5-mononitrate (IS-5-MN, CAS 16051-77-7) were studied after application of Maycor retard 40 (sustained-release capsules, multiple unit formulation, test preparation) in comparison to sustained-release tablets (single unit formulation, reference preparation) with 16 healthy male volunteers in a two-way crossover design. Test and reference formulations were previously characterised in vitro by dissolution tests. ISDN, IS-5-MN (IS-2-MN) plasma concentrations were determined using a selective and sensitive GLC-method with ECD-detection. As pharmacokinetic parameters AUC, Cmax and half value duration (HVD) were evaluated. Bioequivalence was assessed by calculating 90%-confidence intervals (ANOVA, ANOVAlog, Mann-Whitney-test) for ISDN and IS-5-MN. Bioequivalence was accepted if due to the inclusion rule one of the calculated intervals fulfill the requirements of 80 and 120% (AUC) or 70 and 130% (Cmax, HVD), respectively. Relative bioavailability of the test formulation was calculated as 94% (ISDN) and 96% (IS-5-MN). Maximum plasma concentrations of ISDN (IS-5-MN) were determined for the test preparation as 14.3 +/- 3.1 ng/ml (265 +/- 45 45 ng/ml) and as 22.8 +/- 12.6 ng/ml (287 +/- 59 ng/ml) for the reference product. HVD-values were for the test preparation 4.5 +/- 1.3 h (ISDN) and 8.5 +/- 1.3 h (IS-5-MN) and for the reference formulation 3.1 +/- 1.2 h (ISDN) and 8.1 +/- 1.4 (IS-5-MN).(ABSTRACT TRUNCATED AT 250 WORDS)

The influence of different formula diets and different pharmaceutical formulations on the systemic availability of paracetamol, gallbladder size, and plasma glucose.

The influence of two liquid formula diets on the systemic availability of paracetamol was investigated in 12 healthy normal volunteers using a liquid and a solid paracetamol dosage form. The diets contained the same balanced amounts, but different patterns of nutrients and different amounts of dietary fiber. Plasma glucose and gallbladder response to the standard meal were used as indicators of gastric emptying. Paracetamol plasma concentrations following application of the liquid dosage form also served as a marker for the gastroduodenal transport of liquid gastric contents. For the liquid dosage form, the plasma concentration time curves did not vary with diet composition. However, with the tablets, a differential effect was observed. Following coingestion with the fiber depleted diet, the rate of systemic availability was reduced more than with the liquid preparation. A further delay was obvious, when the tablets were combined with the meal enriched in dietary fiber. Plasma glucose and gallbladder response did not vary with diet composition. Variations of gastric emptying are unlikely to account for the variability of food effects. Consequently our results illustrate that an interaction of certain meal components with a particular drug dosage form determines the rate of intragastric release of the active compound. This could be shown due to a high standardization of nutrition by using liquid formula diets. Because of the variation of drug release, paracetamol cannot be used as a marker of gastric emptying without taking into account the vehicle necessary for drug application. In contrast to previous studies, our data provide evidence that even balanced test meals retard paracetamol absorption.(ABSTRACT TRUNCATED AT 250 WORDS)

Gas-liquid chromatography-mass spectroscopy determination of clopamide in plasma.

A gas-liquid chromatography-mass spectroscopy (GLC-MS) method for the determination of clopamide (1) in human plasma was developed to evaluate the pharmacokinetics and bioavailability of 1 in humans. The method is specific, sensitive, and rapid and allows routine analysis as required for extensive pharmacokinetic studies. The assay procedure involves addition of furosemide (2) as an internal standard to plasma, separation on Sep Pack-C18 cartridges, elution by ether: methanol (1:1), evaporation, and subsequent derivatization with trimethylanilinium hydroxide in methanol (Methelute). Then, 5 microL of the reaction mixture is injected into a GLC-MS system which consists of a 1% SE-30 on Gas Chrom Q (100-120 mesh) glass column. The MS information was obtained under the following conditions: ionization beam energy 70 eV, ion source 200 degrees; and m/e 372 for single ion monitoring. The retention times for 1 and 2 were 0.6 and 1.0 min, respectively. The limit of detection is 10 ng/mL of 1 in plasma and the calibration curve was shown to be linear between 10 and 500 ng/mL of 1. After repeated analysis of spiked plasma samples, the coefficient of variation ranged from 5.1 to 8.3%. The recovery from the extraction procedure was 92 +/- 2.2%. Spiked samples frozen at -20 degrees C were stable for at least 8 weeks. The method has been successfully used in a pharmacokinetic study with po dosing of 5 mg of 1 to eight healthy volunteers. Peak plasma concentrations of 197 +/- 56 ng/mL were observed after 1.1 +/- 0.34 h. No measurable concentration of 1 beyond 12 h after dosing was observed.

Clinical chronopharmacology of oral nitrates.

The clinical-chronopharmacological investigations with oral nitrates (ISDN, IS-5-MN) demonstrate that the drugs' pharmacokinetics and/or hemodynamic effects are circadian phase-dependent. For both an immediate-release and a sustained-release preparation of IS-5-MN peak drug concentrations coincided with peak drug effects after morning but not after evening drug application. Results indicate a circadian phase-dependency in the dose-response relationship of oral nitrates.