Acetylation status using hydralazine in African hypertensives at Kenyatta National Hospital.

In this study, the investigation of hydralazine acetylator phenotype was undertaken for the first time in African hypertensives at Kenyatta National Hospital. A total of 25 randomly selected patients with moderate to severe hypertension (diastolic pressure 105-130 mmHg), participated in the phenotyping study. The phenotyping was done by administering oral standard hydralazine dose of 150 mg/day in three divided doses. The 24 hour urinary MTP/hydralazine ratio was used to categorize patients into slow and fast acetylators. Of the patients studied 69.9% were slow acetylators while 30.4% were fast acetylators. The mean 24 hour urinary MTP/hydralazine ratio for slow acetylators was 1.01 +/- 0.95. This was significantly different from the fast acetylators where the mean 24 hour urinary MTP/hydralazine ratio was 10.6 +/- 4.4 (P < 0.001). The acetylator phenotyping divided the patients into two distinct populations and no further arbitrary method was required to divide the patients into either group.

Determination of hydralazine and metabolites in urine by liquid chromatography with electrochemical detection.

The cyclic voltammetric behavior of hydralazine and its primary metabolites, the pyruvate and acetone hydrazones, was examined in the positive potential range at both conventional and electrochemically pretreated glassy carbon electrodes. The enhanced oxidations observed at the treated surface were used as the basis of amperometric electrochemical detection of the compounds following reversed-phase liquid chromatography. The detection limits so obtained at +0.75 V vs. Ag/AgCl (1, 3, and 5 ng injected, respectively) were comparable to those previously reported for absorption and fluorescence detection approaches employing derivatization/preconcentration procedures. For liquid chromatography with electrochemical detection, however, direct quantitation of all three species in urine samples was readily accomplished without any chemical derivatization or sample treatment operations other than particulate filtration.

Effect of dose on acetylator phenotype distribution of hydralazine.

The effect of dose on acetylator phenotype distribution of hydralazine has been determined, The acetylated metabolites methyltriazolophthalazine (MTP) and 3-hydroxymethyltriazolophthalazine (3-OHMTP) and acid-labile hydralazine (HP) were determined in the 0- to 24-hr urine of patients receiving various doses. The difference between the mean value for the ration 3-OHMTP:HP in the rapid and slow acetylators varied with dose, the greatest difference being after a 200 mg (100 mg twice daily) dose. The distribution of the ratio became less clearly bimodal at lower doses, with overlap between phenotypes occurring at doses of 100 mg (50 mg twice daily) or less. The most effective dose for discriminating between acetylator phenotypes was found to be 200 mg (100 mg twice daily).

Quantitative analysis of hydralazine pyruvic acid hydrazone, the major plasma metabolite of hydralazine.

A specific, high-performance liquid chromatographic technique for the measurement of hydralazine pyruvic acid hydrazone is described. This method utilized reversed-phase chromatography for the separation of this hydrophilic metabolite of hydralazine from other fluid constituents present in serum, plasma, or urine of human volunteers and rabbits receiving hydralazine. Detection of the compound of interest is accomplished spectrophotometrically at 250 nm.

Identification and quantitation of hydrazine in the urine of patients treated with hydralazine.

Hydrazine has been identified by gas chromatography-mass spectrometry in the 0- to 24-hr urine of patients administered hydralazine. With a specific gas chromatographic assay procedure, the amount of hydrazine in the 0- to 24-hr urine was determined in patients treated with various doses of hydralazine. The amount of hydrazine detected in the urine was greater in the slow acetylator phenotype than in the rapid acetylator phenotype. Studies indicated that hydrazine was not produced by chemical breakdown of hydralazine or its known metabolites in urine and therefore was unlikely to be a urinary artefact formed by chemical decomposition in the urine.

Metabolism of budralazine, a new antihypertensive agent, III.

1. [14C]Budralazine (I) administered orally to normotensive and spontaneously hypertensive rats showed no significant difference in metabolic fate between the two groups. 2. Peak plasma levels of 14C were 3.6 microgram equiv. of I per ml in both normotensive and hypertensive rats. Approx. 5% of total 14C in the plasma consisted of I within 4 h, but thereafter the parent drug was not detected. Approx. 15% of 14C in the plasma consisted of 1-hydrazinophthalazine within 16 h after the administration. 3. 45% and 37% of the dose of 14C was excreted into urine and faeces within 24 h, respectively. 4. A high retention of 14C in the aorta wall was found and the time course of 14C in the aorta wall was compatible with that of the reduction in blood pressure. The radioactive materials retained in the aorta wall were likely to be I or 1-hydrazinophthalazine, probably the latter, following macroautoradiography in hypertensive rats.

Determination of hydralazine and its metabolites by gas chromatography-mass spectrometry.

Metabolism of the vasodilator hydralazine was investigated by in vivo and in vitro studies. Standards to identify metabolic products were synthesized. Determination and quantification of hydralazine and its metabolites were accomplished by gas chromatography-mass spectrometry. A deuterium-labeled internal standard was used for quantification. 14C-labeled internal standards were synthesized and used to demonstrate recoveries from the biological samples.