Absorption, Distribution and Excretion
Oral administration of hydralazine with food improves its bioavailability. After intravenous injection of 0.3 mg/kg, the AUC is 17.5-29.4 µMmin; after oral administration of 1 mg/kg, the AUC is 4.0-30.4 µMmin. The Cmax of oral hydralazine is 0.12-1.31 µM, depending on the patient's acetylation status. 10% of hydralazine is excreted in feces; 65-90% is excreted in urine. The volume of distribution is 1.34 ± 0.79 L/kg in patients with congestive heart failure and 1.98 ± 0.22 L/kg in patients with hypertension. The clearance of hydralazine primarily occurs extrahepatically—55% in patients with rapid acetylation and 70% in patients with slow acetylation. The mean clearance rate in patients with congestive heart failure was 1.77 ± 0.48 L/kg/h, while the mean clearance rate in hypertensive patients was 42.7 ± 8.9 mL/min/kg. Metabolism/Metabolites Acetylation is a minor metabolic pathway for hydralazine; the major metabolic pathway is hydroxylation, followed by glucuronidation. Five metabolic pathways for hydralazine have been identified. Hydralazine can be metabolized to phthalazine or α-ketoglutarate hydrazone. These metabolites can be further converted to phthalazinones, or hydralazine can be directly metabolized to phthalazinones. Hydralazine can be reversibly converted to the active product hydralazine-acetylasinone. Hydralazine can spontaneously convert to the active product pyruvate hydrazone or its tricyclic dehydration product; these metabolites can interconvert between these two forms. Hydralazine can be converted to hydrazylphthalazinone, which can be further converted to the active product acetylhydrazylphthalazinone. The final metabolic pathway of hydralazine involves conversion to an unnamed hydralazine metabolite, which is further metabolized to 3-methyltriazolamide (MTP). MTP can be metabolized to 9-hydroxymethyltriazolamide or 3-hydroxymethyltriazolamide; the latter can be converted to triazolamide. Known metabolites of hydralazine include the N-acetyl group. The half-life of hydralazine is 2.2–7.8 hours in rapid acetylated individuals and 2.0–5.8 hours in slow acetylated individuals. In patients with heart failure, the half-life of hydralazine is 57–241 minutes, with an average of 105 minutes; in hypertensive patients, the half-life is 200 minutes in rapid acetylated individuals and 297 minutes in slow acetylated individuals. Hydralazine exhibits polymorphic acetylation; slow acetylated individuals typically have higher plasma concentrations of hydralazine, thus requiring lower doses to control blood pressure. However, other factors, such as acetylation, which is a secondary metabolic pathway of hydralazine, can also lead to differences in elimination rates.

Hepatotoxicity
Elevated serum transaminases are uncommon during hydralazine treatment. However, hydralazine has been definitively linked to acute liver injury with jaundice and delayed lupus-like syndrome. Two clinical patterns of liver injury have been described, associated with short latency periods (2 to 6 weeks) or long latency periods (2 months to over a year). Clinically apparent liver injury is usually hepatocellular, but cholestatic patterns have also been reported (Case 1). In short-latency cases, rash, fever, and eosinophilia are common; onset is typically abrupt and severe, but recovery is rapid. In long-latency cases (Case 2), onset is usually more insidious; liver biopsy may resemble chronic hepatitis and show fibrosis, and autoantibodies are often present. Late-stage hepatitis may also be accompanied by lupus-like syndrome induced by hydralazine, especially with high-dose use for 6 months or longer. Recovery may be prolonged. In patients with hepatotoxicity caused by the structure-related antihypertensive drug dihydrozirconium (available in Europe but not in the US), autoantibodies against the P450 system (CYP 1A2) isoenzyme have been identified, and the incidence of hepatotoxicity with dihydrozirconium is higher than with hydralazine.
Probability score: A (Etiology of clinically confirmed liver injury).
Pregnancy and lactation effects
◉ Overview of use during lactation
Limited data on milk and infant serum concentrations, along with a long history of use in postpartum mothers, suggest that hydralazine is an acceptable antihypertensive drug for lactating mothers, including mothers of newborns.
◉ Effects on breastfed infants
No adverse reactions were reported in an 8-week-old breastfed infant.
◉ Effects on lactation and breast milk
No relevant published information found. Found as of the revision date.
Protein binding
hydralazine has a protein binding rate of 87% in serum and may bind to human serum albumin.

[1]. Arce C, Segura-Pacheco B, Perez-Cardenas E, Taja-Chayeb L, Candelaria M, Dueñnas-Gonzalez A. Hydralazine target: from blood vessels to the epigenome. J Transl Med. 2006 Feb 28;4:10.

[2]. Antioxidant activity and inhibitory effects of hydralazine on inducible NOS/COX-2 gene and protein expression in rat peritoneal macrophages. Int Immunopharmacol. 2004 Feb;4(2):163-77.

Hydralazine is a 1-hydrazine derivative of phthalazine, a direct-acting vasodilator used as an antihypertensive drug. It is both an antihypertensive and a vasodilator. Hydralazine belongs to the phthalazine, aza-aromatic, ortho-fused aza-aromatic, and hydrazine classes. Initially developed in the 1950s for the treatment of malaria, hydralazine quickly demonstrated antihypertensive effects and was repurposed for treating other diseases. Hydralazine is a hydrazine derivative vasodilator that can be used alone or as adjunctive therapy for hypertension, but only as adjunctive therapy for heart failure. With the advent of newer antihypertensive drugs, hydralazine is no longer a first-line treatment for these diseases. Hydralazine hydrochloride was approved by the U.S. Food and Drug Administration (FDA) on January 15, 1953. Hydralazine is a small artery vasodilator. Its physiological action is achieved by dilating small arteries. Hydralazine is a commonly used oral antihypertensive drug whose mechanism of action is through inducing peripheral vasodilation. Hydralazine is associated with various acute liver injuries and lupus-like syndromes. Hydralazine has been reported in Achillea pseudopectinata, and relevant data are available. Hydralazine is an phthalazine derivative with antihypertensive effects. It exerts its vasodilatory effect by altering the contractile state of arterial smooth muscle, thereby changing intracellular calcium release and interfering with calcium influx into smooth muscle cells. This drug can also inhibit myosin phosphorylation or chelate trace metals required for smooth muscle contraction, thereby increasing heart rate, stroke volume, and cardiac output. It is a direct-acting vasodilator used as an antihypertensive drug. See also: hydralazine hydrochloride (salt form). Drug Indications Hydralazine can be used alone or as adjunctive therapy for the treatment of essential hypertension. Combination formulations with isosorbide dinitrate can be used as adjunctive therapy for the treatment of heart failure. Mechanism of Action Hydralazine may relax arteriole smooth muscle and lower blood pressure by interfering with calcium transport in vascular smooth muscle through an unknown mechanism. Interference with calcium transport may be achieved by preventing calcium inflow into cells, preventing calcium release from cells, acting directly on actin and myosin, or a combination of these actions. The reduction in vascular resistance leads to an increase in heart rate, stroke volume, and cardiac output. Hydralazine also competes with procollagen prolyl hydroxylase (CPH) for free iron. This competition inhibits CPH-mediated HIF-1α hydroxylation, thereby preventing HIF-1α degradation. Induction of HIF-1α and VEGF promotes endothelial cell proliferation and angiogenesis. Pharmacodynamics Hydralazine relaxes arteriole smooth muscle and lowers blood pressure by interfering with calcium ion transport. The duration of action of hydralazine is short, ranging from 2 to 6 hours. It has a wide therapeutic window, and patients can tolerate doses up to 300 mg. Patients should be informed of the risk of developing systemic lupus erythematosus syndrome.

C8H8N4

160.17592

160.075

86-54-4

Hydralazine hydrochloride;304-20-1

3637

Typically exists as solid at room temperature

1.2583 (rough estimate)

276.07°C (rough estimate)

172ºC

1.5872 (estimate)

1.688

2

4

1

12

150

0

N(=C1C2C(=CC=CC=2)C=NN1)N

RPTUSVTUFVMDQK-UHFFFAOYSA-N

InChI=1S/C8H8N4/c9-11-8-7-4-2-1-3-6(7)5-10-12-8/h1-5H,9H2,(H,11,12)

phthalazin-1-ylhydrazine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)