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The potent antihypertensive properties of hydralazine and dihydralazine prompted the synthesis of sixteen new phthalazine derivatives with thiosemicarbazide or beta-propionamide residues to investigate their possible antihypertensive activity.

The metabolism of dihydralazine sulfate was studied in 11 hypertonic patients treated with that drug chronically. The metabolites were identified in urine with gc, dc, and hplc by comparison with synthesized reference compounds. Following metabolites could be verified: acetylated products, oxidation products, hydrazones and products of decomposition. Products resulting from reaction with nitrites could be not detected.

For the quantitative determination of dihydralazine (1) a derivative with acetylacetone in biological material was formed at pH = 4.9, extracted with n-hexane, and measured gaschromatographically with N-P-FID. Acid labile 1 was hydrolyzed with HCl (1 mol/l) for 24 h. The detection limit was 25 nmol/l plasma. Kinetic studies were performed in 16 patients with essential hypertension under steady-state conditions after the oral application of 50 mg 1. The acetylator phenotype was determined with sulfamethazine. Complete dihydralazine plasma level-time courses were found in only 5 cases. The concentrations were below the detection limit in 4 patients for the whole period. Only single values could be registered in the remaining patients. Maximal plasma levels of the free (58-314 nmol/l) and acid labile 1 (147-367 nmol/l) were reached 20-40 min after the application. The elimination half life was 23-47 min for the free 1, 55-92 min for the acid labile 1. Less than 0.5% of the applied drug were excreted into the 24 h urine in its free form, about 0.4% as acid labile derivatives. No correlation could be found between the acetylator phenotype of the patients and the kinetic behaviour of the drug. Preliminary studies concerning the biliary excretion of 1 after i. m. application in two patients with T-drain showed an accumulation of the free compound with bile/plasma ratios up to 7.4.

Dihydralazine and its metabolites were estimated in the steady-state in 9 hypertonic patients by gas chromatography. Serum levels of both dihydralazine and metabolites were very low and particularly below the detection limit. In urine and faeces about half of the dose was found mainly as metabolites, 2/3 of this in faeces. Acid labile hydrazones of dihydralazine (about 6% of the dose), primary acetylated and primary oxidized metabolites (both about 20%) were identified as main metabolites. Secondary metabolites (hydrazones, acetylated and oxidized products) were measured, too.

Comparative pharmacokinetic studies with high i.v. doses of dihydralazine (1, 5 and 7.5 mg/kg-1, respectively) were performed in rats, rabbits, and dogs. 1 was distributed in rabbits and dogs in two phases with half lives of 0.25-0.4 min and 1.0-2.0 min. The terminal slope was species dependent. The relative clearance values decreased in the order rabbit, rat, dog. High tissue concentrations were observed in rabbits and dogs in parenchymatous organs and endothelium (aorta). Skeletal and heart muscles belonged to the central compartment. The biliary excretion was low in rabbits. Dogs accumulated the drug in bile (bile/serum-ratios = 19-390). Maximally 5% of the given dose were excreted in rabbits with the 12-h-urine.

With respect to their performance a computer aided spectrometric analysis of multicomponent system dihydralazine sulfate hydrochlorothiazide and reserpine was made under various conditions. To find out the advantageous measuring points the difference spectra were determined. The influence of the number of measuring points, the single and mixture calibration and the dimensiation of calibration matrix to accuracy and precision was investigated and the limits of the determination for the three component system are discussed.