Plasma concentration and acetylator phenotype determine response to oral hydralazine

Hypertension (Impact Factor: 6.48). 09/1981; 3(5):580-5. DOI: 10.1161/01.HYP.3.5.580
Source: PubMed

ABSTRACT The vasodepressor response to single and multiple oral doses of hydralazine, 1 mg/kg, was studied in hypertensive patients. The concentration of hydralazine in plasma was measured both by a newly developed specific and a nonspecific assay similar to those used in previous studies. Acetylator phenotype was determined following oral sulfamethazine. Plasma hydralazine concentration peaked at 1 hour after administration and was undetectable 2 hours later. Apparent hydralazine was present in plasma in higher concentration and for a longer duration than hydralazine. The peak decreases in blood pressure (BP) were proportional to plasma hydralazine concentration following administration of both single and multiple doses and were substantially maintained for 8 hours. In contrast there was no significant correlation between decreases in BP and apparent hydralazine concentrations. The plasma concentration of hydralazine after a standard oral dose varied by as much as 15-fold among individuals and was lower in rapid than slow acetylator phenotype patients. The BP responses were positively correlated with plasma hydralazine concentrations and inversely correlated with acetylator indices. Low plasma concentrations may account for poor responses of some patients to conventional oral doses of hydralazine. The applicability of acetylator phenotyping for individualization of hydralazine dosage regimens merits further evaluation.

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    ABSTRACT: The efficacy and toxicity of hydralazine differ widely among individual patients, possibly because of different sensitivities to drug effect or as a reflection of pharmacokinetic differences. Therefore, the variability in plasma hydralazine concentrations after single intravenous and single and multiple oral doses was studied in 9 male hypertensive patients. After an intravenous dose of 0.3 mg/kg the area under the plasma concentration time curve (AUC) varied over less than a twofold range 17.5-29.5 muM-minute. However, after a single oral dose, 1 mg/kg, and after at least the fifth dose of a regimen consisting of 1 mg/kg given every 12 hours, there were much wider variations in AUC values: 4.0-30.4 and 3.2-38.5 muM-minute, respectively. Similar ranges in peak hydralazine concentration, Cp, were also noted, 0.12-1.31 muM after single oral dose and 0.10-1.39 muM after the multiple dose regimen. A significant portion of the observed interpatient variability could be explained by differences in acetylation ability. The AUC and Cp values for both the single and multiple oral doses were significantly lower (P less than 0.001) in rapid than in slow acetylators. Therefore, determining the acetylation ability of patients requiring hydralazine may help to optimize therapeutic benefit and minimize toxicity.
    Arthritis & Rheumatology 08/1981; 24(8):987-93. DOI:10.1002/art.1780240802 · 7.76 Impact Factor
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    ABSTRACT: Hydralazine is one of the most frequently prescribed drugs for the treatment of moderate to severe hypertension. In addition, it is being used increasingly for the treatment of congestive heart failure when more traditional approaches fail. Although hydralazine has been in clinical use for 30 years, there is insufficient information concerning dose-blood concentration and blood concentration-response relationships to formulate rational approaches for dosage individualisation. This paucity of data is primarily due to the fact that many previous methods for measurement of hydralazine in plasma were non-selective and measured circulating, inactive metabolites. Recently, more selective procedures have been developed and are being applied to the study of the pharmacokinetic behaviour of hydralazine in man. Hydralazine is very unstable in plasma in vitro (half-life of approximately 6 minutes at 37°C) and derivatisation of samples must be carried out very rapidly to avoid loss of drug. Studies in healthy volunteers and hypertensive patients indicated that after oral administration hydralazine undergoes extensive acetylator phenotype-dependent first-pass metabolism. Results using selective assay procedures indicate a mean fractional availability of about 0.30 to 0.35 for slow acetylators and 0.10 to 0.16 for rapid acetylators. Food may enhance the bio-availability. There is evidence that the first-pass effect is saturable. After intravenous administration acetylator phenotype is not a major determinant of hydralazine disposition. This indicates that a large fraction of systemic clearance is via metabolic pathways independent of acetylator phenotype. The fact that hydralazine rapidly forms a hydrazone with pyruvic acid in plasma or whole blood can account for a significant proportion of systemic clearance. However, formation of other hydrazones or adducts cannot be ruled out. Besides acetylation, oxidative metabolism accounts for a significant proportion of elimination since 4-(2-acetylhydrazino) phthalazin-1-one is a major urinary metabolite. This compound can only occur if oxidation precedes acetylation since the product of hydralazine acetylation is 3-methyl-s-triazolo [3,4a] phthalazine and would not yield the 2-acetylhydrazino derivative upon subsequent oxidation. Less than 10% of a dose is present in urine as hydralazine or acid-labile conjugates of hydralazine. Clearance and apparent volume of distribution appear to be lower and half-life longer in older hypertensive patients than in young healthy volunteers, but the 2 populations were studied by different research groups using different experimental designs and different assay methods. Further studies are needed to determine whether the differences really exist. Similarly, the effects of renal failure on the pharmacokinetics of hydralazine are not yet understood. In addition, the use of hydralazine in resistant congestive heart failure requires that the influences of this disease stale on kinetics be determined. Hydralazine has been shown to increase the bioavailability of propranolol and may similarly influence other drugs that undergo significant first-pass metabolism. Although there is not a temporal relationship between antihyperlensive response and plasma hydralazine concentrations, the maximal change in mean arterial pressure correlates in magnitude with either the peak hydralazine concentration or the area under the plasma hydralazine concentration-lime curve. It appears that determination of acetylation ability may serve as a practical guide for individualisation of oral hydralazine dosage regimens.
    Clinical Pharmacokinetics 01/1982; 7(3):185-205. DOI:10.2165/00003088-198207030-00001 · 5.05 Impact Factor
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