Comparative studies of drotaverine--acephyllinate (Depogen) and pentoxifylline (Trental).

Pentoxifylline is an orally active agent for the treatment of peripherial and cerebral vascular diseases. Pentoxifylline increases the deformability of red blood cells in vitro, reduces blood viscosity and decreases platelet aggregation and thrombus formation. Depogen has shown antiaggregatory effect both in vitro and in ex vivo. The inhibitory effect of Pentoxifylline was about 3-5 times weaker than that of Depogen. IC50 = 900/micrograms/ml for Depogén and 3600/micrograms/ml for Pentoxifylline on human platelet rich plasma. Depogen has shown ex vivo antiaggregatory effect on anesthetised rabbits, ID50 = 7 mg/kg in case of iv. administration, and ID50 = 300 mg/kg in case of orally administration. Both compound inhibit the release of platelet precoagulation factor, but the effect of Pentoxifylline was slighter.

A new method for high-performance liquid chromatographic determination of drotaverine in plasma.

A sensitive, specific high-performance liquid chromatographic procedure was developed for the determination of plasma drotaverine levels. Basic plasma samples were adjusted to pH 1.5 and extracted with chloroform. HPLC [n-heptane-dichloromethane-diethylamine (50:25:2)] on a microporous silica column, with a variable-wavelength UV detector set at 302 nm allowed the measurement of drotaverine at the 50-ng/mL level. The utility of this method for determination of drotaverine in dog and rat plasma was demonstrated.

Correlation between disintegration, dissolution and in vivo absorption rate in the case of compounds with benzyl-isoquinoline structures and its pharmacokinetic aspects.

Investigations have proved that in the case of po preparations disintegration time, dissolution rate and in vivo absorption rate are closely interrelated. These correlations described by adequate mathematical formulas are valid in the case of papaverine, drotaverine and Depogen--compounds with benzyl-isoquinoline structure.

Biopharmaceutical aspects of Depogen.

The absorption of Depogen was studied on an in vitro model and in various laboratory animals using stoichiometrically equivalent doses of drotaverin (No-Spa) calculated for drotaverin base for comparison. Blood levels of the drug were assessed by radiochemical and microchemical methods. Based on the results obtained and pharmacokinetic properties, the expectable optimal dosage and formulations for the possible field of indication were elaborated.

The absorption and excretion rates of a new pyrido[1,2-a] pyrimidine derivative (Chinoin 123) in rats.

The metabolism and absorption of a potential new drug, Chinoin 123, having an antiatherogenic effect, were studied in rats. Using different methods it was confirmed that the main metabolite of the drug is a free acid form, formed by ester hydrolysis. In Sartorius Resorption Model only the gastric absorption was confirmed and calculated. In vivo experiments in rats showed rather good absorption. The blood and urine concentrations of the drug were determined.

The fate of Depogen in rats.

Studying the metabolism of Depogen in rats we have worked out a method for the purification, isolation and separation of the drug and its potential metabolites. In the basic fraction we have found the same metabolic pathway of Drotaverin published earlier by us. In the focus of our recent work was the fate of the theophylline-7-acetic acid and its eventual biotransformed products. We have stated that theophylline-7-acetic acid contrasts with the theophylline excresa in unchanged form, which has been confirmed by several methods.

Data on the metabolism of benzylisoquinoline derivatives. The metabolism of drotaverin.

Studying the metabolism of drotaverin (No-Spa¿), we have elaborated a method for the isolation, purification and separation of metabolites and of drotaverin excreted in unchanged form in the urine and feces. The structure of the chief metabolites was cleared by t.l.c., polarography, UV spectrophotometry, and mass spectrometry. It was stated that beside drotaverin excreted in unchanged form, the biotransformation of the molecule results in the formation of oxidation and desalkylation products.