Hydralazine, metabolites

The biotransformation of hydrazine and hydrazide derivatives also proceeds by acetylation. The antihypertensive hydralazine (Apresoline) " ""and the MAO inhibitor phenelzine (Nardil) " are two representative hydrazine compounds that are metabolized by this pathway. The initially formed N-acetyl derivative of hydralazine is unstable and cyclizes intramolecularly to form 3-methyl-s-triazolo 3.4-a phtha-lazine as the major isolable hydralazine metabolite in humans. " The antituberculosis drug isoniazid or isonicoli-nic acid hydrazide (INH) is metabolized extensively to N-acetylisoniazid. " ... 

Facchini, V., and Timbrell, J. A. Determination of Hydralazine Metabolites 4-Hydrazinophthalazin-l-one and N-Acetylhydrazinophthalazin-1-... 

Identification of 3-Methyl-s-tri-azolo[3,4-a]phthalazine, a Human Hydralazine Metabolite, by Gas Chromatography-Mass Spectrometry Arzneim.-Forsch. 23(8) 1028-1029 (1973) GA 80 22460d... 

The ability of hydralazine and similar hydrazino compounds to reduce blood pressure was reported by Gross et al (1) in 1950. Methods of synthesis were published by Druey and Ringier (2) in 1951, along with typical reactions displayed by the compound, including several reactions which later became the bases for analysis of hydralazine and its metabolites. The drug has been widely used for treatment of hypertension, and papers on its properties and methods for its determination have been published in many languages. 

The same procedure, or modifications of it, was used by Zak et al (80), Talseth (42,82,82,83), and Haegele et al (46) for metabolic studies. Zak et al (80) point out that hydrolysis of conjugates of the drug may cause analytical results on biological samples to be variable, depending on the acid concentration during derivatization, and that selective analysis for unchanged hydralazine and acid-labile metabolites can be carried out by suitable adjustment of the acid concentration. 

Pharmacokinetics Hydralazine is rapidly absorbed after oral use. Half-life is 3 to 7 hours. Protein binding is 87%, and bioavailability is 30% to 50%. Plasma levels vary widely among individuals. Peak plasma concentrations occur 1 to 2 hours after ingestion duration of action is 6 to 12 hours. Hypotensive effects are seen 10 to 20 minutes after parenteral use and last 2 to 4 hours. Slow acetylators generally have higher plasma levels of hydralazine and require lower doses to maintain control of blood pressure. Hydralazine undergoes extensive hepatic metabolism it is excreted in the urine as active drug (12% to 14%) and metabolites. 

Minoxidil (Loniten) is an orally effective vasodilator. It is more potent and longer acting than hydralazine and does not accumulate significantly in patients with renal insufficiency. It depends on in vivo metabolism by hepatic enzymes to produce an active metabolite, minoxidil sulfate. Minoxidil sulfate activates potassium channels, resulting in hyperpolarization of vascular smooth muscle and relaxation of the blood vessel. 

Minoxidil is a very efficacious orally active vasodilator. The effect results from the opening of potassium channels in smooth muscle membranes by minoxidil sulfate, the active metabolite. Increased potassium permeability stabilizes the membrane at its resting potential and makes contraction less likely. Like hydralazine, minoxidil dilates arterioles but not veins. Because of its greater potential antihypertensive effect, minoxidil should replace hydralazine when maximal doses of the latter are not effective or in patients with renal failure and severe hypertension, who do not respond well to hydralazine. 

The heme iron in the peroxidase is oxidized by the peroxide from III+ to V4- in compound I. The compound I is reduced by two sequential one-electron transfer processes giving rise to the original enzyme. A substrate-free radical is in turn generated. This may have toxicological implications. Thus the myeloperoxidase in the bone marrow may catalyze the metabolic activation of phenol or other metabolites of benzene. This may underlie the toxicity of benzene to the bone marrow, which causes aplastic anemia (see below and chap. 6). The myeloperoxidase found in neutrophils and monocytes may be involved in the metabolism and activation of a number of drugs such as isoniazid, clozapine, procainamide, and hydralazine (see below). In in vitro systems, the products of the activation were found to be cytotoxic in vitro. 

For example, it has been suggested that the adverse reactions caused by a number of drugs such as isoniazid, procainamide, hydralazine could be due to metabolic activation by myeloperoxidase in neutrophils. Thus neutrophils will metabolize procainamide (Fig. 4.38) to a hydroxylamine metabolite. In the presence of chloride ion, myeloperoxidase will produce hypochlorous acid, a strong oxidizing agent, which may be responsible for metabolic activation and toxicity. One of the products is N-chloroprocainamide (see also sect. "Hydralazine," chap. 7). 

Disposition in the Body. Readily absorbed after oral administration. It undergoes first-pass acetylation, the extent of which is genetically determined bioavailability 30 to 35% in slow acetylators, 10 to 16% in rapid acetylators. The major metabolites are 3-methyl-l,2,4-triazolo[3,4-a]phthalazine (MTP—the acetylation product) hydralazine pyruvic acid hydrazone (HPH) which is the major plasma metabolite 4-(2-acetylhydra-zino)phthalazin-l-one (A-AcHPZ) which is the major urinary metabolite 3-hydroxymethyl-1,2,4-triazolo[3,4-a]phthalazine (3-OHMTP). About 65% of a dose is excreted in the urine in 24 hours. In rapid acetylators, about 30% is excreted as A-AcHPZ and 10 to 30% as conjugated 3-OHMTP in slow acetylators, about 15 to 20% is excreted as A-AcHPZ and up to 10% as conjugated 3-OHMTP. Other metabolites include phthalazin-1-one (PZ), 1,2,4-triazolo[3,4-fl]phthalazine (TP), 9-hydroxy-MTP, phthalazine, tetrazolo[5,l-a]phthalazine, and hydrazones of hydralazine formed with acetone and a-ketoglutaric acid. About 10% of a dose is eliminated in the faeces. 

The mechanism by which hydralazine causes these effects is not known but it seems that the immune system is involved. Slow metabolizers may be more susceptible because they will maintain higher levels of the unchanged drug in the body which, hke penicillin, is fairly unstable. There is other evidence that alternative routes of metabolism may be more important in the slow metaboHzers, producing other reactive metabolites. 

Minoxidil is a vasodilator selective for arterioles rather than for veins, similar to diazoxide and hydralazine. Like the former, it acts through its sulphate metabolite as an ATP-dependent potassium channel opener. It is highly effective in severe hypertension, but causes increased cardiac output, tachycardia, fluid retention and hypertrichosis. The hair growth is generalised and although a cosmetic problem in women, it has been exploited as a topical solution for the treatment of baldness in men. 

Exposure. Methods are available for determining the levels of hydrazine in the plasma of humans (Blair et al. 1985), and the levels of all three hydrazines and their metabolites and in tissues, urine, and expired air of animals (Alvarez de Laviada et al. 1987 Back et al. 1963 Dost et al. 1966 Fiala et al. 1976 Harbach and Swenberg 1981 Kaneo et al. 1984 Kang et al. 1988 Matsuyama et al. 1983 Preece et al. 1991 Reed et al. 1963 Springer et al. 1981). The detection of hydrazines and some of their metabolites (for example, the metabolites of 1,2-dimethylhydrazine-azoxymethane and methylazoxymethanol) are fairly specific for exposures to hydrazines. However, it should be kept in mind that treatment with certain drugs such as isoniazid or hydralazine can result in the presence of hydrazine in human plasma... 

The mechanism of hydralazine-induced LE is not currently understood but the evidence available indicates that it has an immunological basis. Hydralazine is a chemically reactive molecule and it is also metabolized to reactive metabolites, possibly free radicals, by the cytochromes P-450 system (figure... 

Thus interaction of hydralazine or a metabolite with macromolecules may underlie the immune response. An alternative or additional hypothesis involves inhibition of the complement system. The complement system helps remove immune complexes by solubilization, but if it is inhibited deposition and accumulation of such complexes would be increased. Hydralazine and some of its metabolites interfere with part of the complement system, inhibiting the covalent binding of complement C4 by reaction with the thioester of activated C4. However, the conentrations required are high relative to the normal therapeutic concentration. More recently it has been shown that hydralazine inhibits DNA methylation in the T-cell. The inhibition of DNA methyl transferase may initiate immune reactions via activation of genes as a result of this interference with DNA methylation. However, although the mechanism of hydralazine-induced LE is not yet understood, it is an important example of drug-induced toxicity for two reasons ... 

Hydralazine. Vasodilator drug which causes systemic lupus erythematosus in a significant proportion of patients. Several predisposing factors have been identified dose (>25 mg) duration of therapy (mean 18 months) acetylator phenotype (slow) HLA type (DR4) gender (females males, 4 1). Antinuclear antibodies and antihydralazine antibodies detected in serum. Causes a Type III immune reaction. Mechanism is unclear but may involve reaction of parent drug or metabolite with protein. Interference with the complement system and interaction with nucleic acids also occur. Metabolism also may be mediated by myeloperoxidase in activated neutrophils. 

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