Hydralazine metabolism

Hydralazine hydrochloride is rapidly metabolized and excreted. Experiments with carbon-14 labeled drug in humans indicated that less than 10 percent of the intact drug was excreted (36). Within 5 days after a dose, 83 to 89 percent was excreted in the urine and 9 to 12 percent in the feces. Of the material excreted in the urine, 96 percent was recovered in the first 24 hours. Individuals who are slow acetylators exhibit higher hydralazine blood levels than fast acetylators, for the same dose (37) ... 

Reported metabolic products of hydralazine in various species are as follows ... 

Figure 11 is a scheme illustrating the metabolism of hydralazine, based primarily on those proposed by Haegele et al (46) and Wagner et al (36). 

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. 

CYP450 antibodies leading to autoimmune hepatitis [68,69], Metabolic activation can also occur within the monocyte/macrophage and has been reported for many of the same xenobiotics (e.g., hydralazine) suggesting multiple mechanisms for xenobiotic autoimmune potential [68],... 

Hofstra, A. and Uetrecht, J.P., Metabolism of hydralazine to a reactive intermediate by the oxidizing system of activated leukocytes, Chemico-Biol. Interact., 89,183, 1993. 

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. 

The major pathways for its metabolism include ring hydroxylation, with subsequent glucuronide conjugation and A-acetylation. Hydralazine exhibits a first-pass effect in that a large part of an orally administered dose is metabolized before the drug reaches the systemic circulation. The first-pass metabohsm occurs in the intestinal mucosa (mostly A-acetylation) and the hver. The primary excretory route is through renal elimination, and about 80% of an oral dose appears in the urine within 48 hours. About 10% is excreted unchanged in the feces. 

The plasma half-life of hydralazine may be increased fourfold or fivefold in patients with renal failure. If renal failure is present, therefore, both the antihypertensive and toxic effects of hydralazine may be enhanced. Since A-acetylation of hydralazine is an important metabolic pathway and depends on the activity of the enzyme A-acetyltransferase, genetically determined differences in the activity of this enzyme in certain individuals (known as slow acetylators) wih result in higher plasma levels of hydralazine therefore, the drug s therapeutic or toxic effects may be increased. 

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. 

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). 

The LE syndrome only develops in those patients with the slow acetylator phenotype. Metabolic studies have shown that the metabolism of hydralazine involves an acetylation step (Fig. 7.82), which is influenced by the acetylator phenotype. 

Figure 7.82 Some of the major routes of metabolism of hydralazine. As well as cyp-mediated oxidative metabolism, myeloperoxidase (MPO) in neutrophils will also oxidize the drug as shown.

Figure 7.83 Possible routes for the metabolic activation of hydralazine. The oxidation of the hydrazine group may also involve the formation of a nitrogen-centered radical, which could also give rise to phthalazine with loss of nitrogen.

Timbrell JA, Facchini V, Harland SJ, et al. Hydralazine-induced lupus is there a toxic metabolic pathway Eur J Clin Pharmacol 1984 27 555. 

Runge-Morris, M., Feng, Y, Zangar, R.C. Novak, R.F. (1996) Effects of hydrazine, phenelzine, and hydralazine treatment on rat hepatic and renal drug-metabolizing enzyme expression. DrugMetab. Disp., 24, 734-737... 

Substances that can be metabolized to y-diketones, such as -hexane, which is metabolized to 2,5-hexanedione, cause the same disorders. Examples of the many other substances known to cause axonopathies are colchicine, disulhram, hydralazine, misonidazole, and insecticidal pyrethroids. Peripheral neuropathy is the most common kind of axonopathic disorder. However, other symptoms may be observed. Numerous cases of manic psychoses were produced in workers exposed to carbon disulfide, CS2, in the viscose rayon and vulcan rubber industries. 

---