Metabolism of Hydralazine

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). 

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. 

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.

Streeter AJ, Timbrell JA. The in vitro metabolism of hydralazine. Drug Metab Dispos... 

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

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 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. 

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.

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. " ... 

Okunieff, P., Kallinowski, F., Vaupel, P., and Neuringer, L. J. (1988) Effects of hydralazine-induced vasodilation on the energy metabolism of murine tumors studied by in vivo 31P-nuclear magnetic resonance spectroscopy. J. Natl. Cancer. Inst. 80, 745-750. 

Genetic polymorphisms of xenobiotic-metabolizing enzymes may result in expression of inactive enzymes or enzymes with a reduced or increased metabolic activity (Daly, 1995). For example, the incidence of hydralazine- and procainamide-induced lupus is higher or the disease starts earlier in individuals with the slow acetylator phenotype caused by mutant NAT-2 alleles than in individuals exhibiting the fast-acetylator phenotype (Woosley et al., 1978 von Schmiedeberg et al., 1999). 

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... 

First-pass acetylation in the Gl mucosa and liver is related to genetic acetylator phenotype (8). Acetylation phenotype is an important determinant of the plasma concentrations of hydralazine when the same dose of hydralazine is administered orally. Slow acetylators have an autosomal recessive trait that results in a relative deficiency of the hepatic enzyme N-acetyl transferase, thus prolonging the elimination half-life of hydralazine (see Chapter 10). This population of hypertensive patients will require an adjustment in dose to reduce the increased overactive response. Approximately 50% of African Americans and Caucasians, and the majority of American Indians, Eskimos, and Orientals are rapid acetylators of hydralazine. This population of patients will have subtherapeutic plasma concentrations of hydralazine because of its rapid metabolism to inactive metabolites and shorter elimination times. Patients with hydralazine-induced systemic lupus erythematosus frequently are slow acetylators. 

Differences in metabolism among patients can lead to differences in susceptibility to ADRs e.g. patients with abnormal pseudocholinesterase levels have prolonged apnea after receiving succi-nylcholine patients with low activity of A-acetyl transferase are more likely to develop lupus-like reactions to procainamide, hydralazine, and isonia-zid and variants of the cytochrome P-450 family of enzymes can lead to altered metabolism of a variety of drugs, including antidepressants, antiarrhythmic agents, codeine, metoprolol terfenadine, cyclosporine, calcium channel blockers, and others (Peck et al 1993). 

The same inheritance controls the acetylation (deactivation) of the antibacterial sulfonamides, the anti-arrhythmic cardiac drug, procainamide (7.56) (Woosley et aL, 1978), the blood-pressure-lowering drug, hydralazine 11.47), and the amine derived by metabolism of the sedative, nitrazepam (12.98). In each case, rapid acetylation reduces the effect of the drug, but slow acetylators of hydralazine are unfortunate for they are prone to develop systemic lupus erythematosis, with arthritis-like symptoms (Batchelor a/., 1980). 

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