Hydroxyurea

Absorption

After oral administration hydroxyurea is readily absorbed from the gastrointestinal tract. Peak plasma concentrations are reached within 2 hours and by 24 hours the serum concentrations are virtually zero. Bioavailability is complete or nearly complete in cancer patients.
After oral administration of 20 mg/kg of hydroxyurea, a rapid absorption is observed with peak plasma levels of about 30 mg/L occurring after 0.75 and 1.2 h in children and adult patients with sickle cell syndrome, respectively. The total exposure up to 24 h post-dose is 124 mg.h/L in children and adolescents and 135 mg.h/L in adult patients. The oral bioavailability of hydroxyurea is almost complete as assessed in indications other than sickle cell syndrome.
In a comparative bioavailability study in healthy adult volunteers (n=28), 500 mg of hydroxyurea oral solution was demonstrated to be bioequivalent to the reference 500 mg capsule, with respect to both the peak concentration and area under the curve. There was a statistically significant reduction in time to peak concentration with hydroxyurea oral solution compared to the reference 500 mg capsule (0.5 versus 0.75 hours, p = 0.0467), indicating a faster rate of absorption.[L47137
In a study of children with Sickle Cell Disease, liquid and capsule formulations resulted in similar area under the curve, peak concentrations, and half-life. The largest difference in the pharmacokinetic profile was a trend towards a shorter time to peak concentration following ingestion of the liquid compared with the capsule, but that difference did not reach statistical significance (0.74 versus 0.97 hours, p = 0.14).

Toxicity

Oral, mouse: LD50 = 7330 mg/kg; Oral, rat: LD50 = 5760 mg/kg Teratogenicity: Teratogenic effects have occurred in experimental animals.Hydroxyurea use during a small number of human pregnancies has been reported. Adverse effects have not been observed in any of the exposed newborns. Reproductive Effects: Adverse reproductive effects have occurred in experimental animals. Mutagenicity: Mutagenic effects have occurred in experimental animals.Mutagenic effects have occurred in humans.

Description

Readily oxidized in vivo to free radical forms, which destroy the stable tyrosyl free radical of the metalloenzyme ribonucleotide reductase, suppressing deoxyribonucleotide production and blocking DNA synthesis and repair.1,2 Reduces cell proliferation, and causes S-phase arrest and death.3 Induces p53-dependent NF-κB target gene expression in U2OS cells expressing HA-RelA.4 Stimulates fetal hemoglobin production in vitro and in vivo.5 Allows for S phase enrichment of CHO cells with maintenance of viability for enhanced site-specific genome engineering.6 Anticancer and antiviral agent.

Chemical properties

Off-White Crystalline Solid

Originator

Hydrea,Squibb,UK,1967

The Uses of Hydroxyurea

An anti-neoplastic - inhibits ribonucleoside reductase and DNA replication. A potential therapy for sickle cell anemia which involves the nitrosylation of sickle cell hemoglobin. Horseradish peroxidase catalyzes nitric oxide formation from hydroxyurea in the presence of hydrogen peroxide.

The Uses of Hydroxyurea

antineoplastic, inhibits ribonucleoside diphosphate reductase

The Uses of Hydroxyurea

Hydroxyurea USP is used to treat Chronic granulocytic leukemia; melanoma; cancer of ovary, head, neck.

Background

An antineoplastic agent that inhibits DNA synthesis through the inhibition of ribonucleoside diphosphate reductase.

Indications

Hydroxyurea is indicated to reduce the frequency of painful crises and to reduce the need for blood transfusions in adult and pediatric patients, 2 years of age and older, with sickle cell anemia with recurrent moderate to severe painful crises.

What are the applications of Application

Hydroxyurea is an antineoplastic agent that inhibits DNA synthesis via ribonucleotide reductase inhibition.

Indications

Hydroxyurea (Hydrea) inhibits the enzyme ribonucleotide reductase and thus depletes intracellular pools of deoxyribonucleotides, resulting in a specific impairment of DNA synthesis. The drug therefore is an Sphase specific agent whose action results in an accumulation of cells in the late G1- and early S-phases of the cell cycle.

Definition

ChEBI: Hydroxyurea is a member of the class of ureas that is urea in which one of the hydrogens is replaced by a hydroxy group. An antineoplastic used in the treatment of chronic myeloid leukaemia as well as for sickle-cell disease. It has a role as a DNA synthesis inhibitor, an EC 1.17.4.1 (ribonucleoside-diphosphate reductase) inhibitor, an antineoplastic agent, a genotoxin, an antimetabolite, a teratogenic agent, a radical scavenger, an immunomodulator and an antimitotic. It is a member of ureas and a one-carbon compound.

Manufacturing Process

The procedure may be illustrated by the following equations relating to the preparation of hydroxyurea from hydroxylamine hydrochloride:
(1) R4N+Cl-+ NaNCO = R4N+NCO-+ NaCl
(2) R4N+NCO-+ H2NOH HCl = R4N+Cl-+HONH-CO-NH2
Equation (1) shows the simple conversion of a quaternary ammonium anion exchange resin from the chloride form to the cyanate form. Equation (2) shows the reaction of the resin in the cyanate form with hydroxylamine hydrochloride whereby hydroxyurea is formed and the anion Cl-is retained by the quaternary resin.
A 90 x 6 cm column was packed with 2 kg of granular Amberlite IRA-410 resin in the chloride form (a vinylpyridine/divinylbenzene copolymer quaternized with dimethyl sulfate and converted to chloride) and washed with 3 kg of a 10% aqueous solution of sodium cyanate. This changed the resin from the chloride to the cyanate form. Sodium chloride and excess sodium cyanate were then washed from the column with distilled water until the effluent failed to give a white precipitate with silver nitrate. The reaction of equation (2) was conducted by elutriating the column with a solution of 105 grams (1.5 mols) of hydroxylamine hydrochloride in 400 ml water at about 15°C.
A hot (50° to 70°C) reaction zone developed near the top of the column and about 30 minutes was required for this hot zone to descend the full length of the column. The reaction solution was followed in the column by 2.5 liters of distilled water. Collection of the product was begun when hydroxyurea could be detected in the effluent, as indicated by a black precipitate on warming a sample with a silver nitrate test solution. All the effluents were combined and vacuum evaporated at 35°C to give 90 grams of tan residue corresponding to 79% yield of crude product. After recrystallization from 100 ml of water heated to 75°C, the colorless product was dried in a vacuum desiccator over phosphorus pentoxide to give 60.6 grams (53% yield) of hydroxyurea, MP 133° to 136°C.

Therapeutic Function

Cancer chemotherapy

General Description

Odorless or almost odorless white to off-white crystalline solid. Tasteless.

General Description

HONH-CO-NH₂. The drug is available in a 500-mg capsulefor oral use. Hydroxyurea is often considered an antimetabolitedrug, and it is used to treat myelogenousleukemia, ovarian cancer, and essential thrombocytosis. Themechanism of action of hydroxyurea involves inhibition ofDNA biosynthesis by inhibition of the enzyme ribonucleotidereductase). Resistance can occur viaincreased expression of ribonucleotide reductase. The oralbioavailability is quite high approaching 100% and the drugis distributed to all tissues. Hydroxyurea readily enters theCNS and distributes to human breast milk. A major portionof the total dose is excreted unchanged in the urine. Thedrug has been shown to increase the toxicity of 5-FU, andhydroxyurea may increase the effectiveness of some antimetaboliteHIV drugs. The toxicity profile includes myelosuppression,leucopenia, nausea, vomiting, pruritus hyperpigmentation,headache, drowsiness, and confusion.

Air & Water Reactions

Water soluble.

Reactivity Profile

An amide. Amides/imides react with azo and diazo compounds to generate toxic gases. Flammable gases are formed by the reaction of organic amides/imides with strong reducing agents. Amides are very weak bases (weaker than water). Mixing amides with dehydrating agents such as P2O5 or SOCl2 generates the corresponding nitrile. The combustion of these compounds generates mixed oxides of nitrogen (NOx).

Fire Hazard

Flash point data for Hydroxyurea are not available; however, Hydroxyurea is probably combustible.

Biochem/physiol Actions

Anti-neoplastic. Inactivates ribonucleoside reductase by forming a free radical nitroxide that binds a tyrosyl free radical in the active site of the enzyme. This blocks the synthesis of deoxynucleotides, which inhibits DNA synthesis and induces synchronization or cell death in S-phase.

Mechanism of action

Hydroxyurea is rapidly absorbed after oral administration, with peak plasma levels achieved approximately 1 to 2 hours after drug administration; its elimination half-life is 2 to 3 hours. The primary route of excretion is renal, with 30 to 40% of a dose excreted unchanged.

Pharmacokinetics

Hydroxyurea has dose-dependent synergistic activity with cisplatin in vitro. In vivo Hydroxyurea showed activity in combination with cisplatin against the LX-1 and CALU-6 human lung xenografts, but minimal activity was seen with the NCI-H460 or NCI-H520 xenografts. Hydroxyurea was synergistic with cisplatin in the Lewis lung murine xenograft. Sequential exposure to Hydroxyurea 4 hours before cisplatin produced the greatest interaction.

Clinical Use

Hydroxyurea is used for the rapid lowering of blood granulocyte counts in patients with chronic granulocytic leukemia. The drug also can be used as maintenance therapy for patients with the disease who have become resistant to busulfan. Only a small percentage of patients with other malignancies have had even brief remissions induced by hydroxyurea administration.

Side Effects

Hematological toxicity, with white blood cells affected more than platelets, may occur. Megaloblastosis of the bone marrow also may be observed. Recovery is rapid, generally within 10 to 14 days after discontinuation of the drug. Some skin reactions, including hyperpigmentation and hyperkeratosis, have been reported with chronic treatment.

Synthesis

Hydroxyurea (30.6.1) is made by reacting sodium cyanate with hydroxylamine. In this reaction, hydroxylamine hydrochloride and a basic ion-exchange resin are used.

Veterinary Drugs and Treatments

Hydroxyurea may be useful in the treatment of polycythemia vera, mastocytomas, and leukemias in dogs and cats. It is often used to treat dogs with chronic myelogenous leukemia no longer responsive to busulfan. Hydroxyurea, potentially, may be of benefit in the treatment of feline hypereosinophilic syndrome and in the adjunctive treatment of canine meningiomas. It can also be used in dogs for the adjunctive medical treatment (to reduce hematocrit) of right to left shunting patent ductus arteriosis or tetralogy of Fallot.

Drug interactions

Potentially hazardous interactions with other drugs
Antipsychotics: avoid with clozapine, increased risk of agranulocytosis.
Antivirals: increased toxicity with didanosine and stavudine - avoid.
Vaccines: risk of generalised infections - avoid.

Metabolism

Up to 60% of an oral dose undergoes conversion through saturable hepatic metabolism and a minor pathway of degradation to acetohydroxamic acid by urease found in intestinal bacteria.

Metabolism

Hydroxyurea has excellent oral bioavailability (80–100%), and serum levels peak within 2 hours of consuming the capsules. If a positive response is noted within 6 weeks, toxicities generally are mild enough to permit long-term or indefinite therapy on either a daily or every-3-day basis. Leukopenia and, less commonly, thrombocytopenia and/or anemia are the most serious adverse effects. Excretion of the unchanged drug and the urea metabolite is via the kidneys. The carbon dioxide produced as a by-product of hydroxyurea metabolism is excreted in the expired air.

Purification Methods

Recrystallise hydroxyurea from absolute EtOH (10g in 150mL). Note that the rate of solution in boiling EtOH is slow (15-30minutes). It should be stored in a cool dry place, but some decomposition could occur after several weeks. [Deghenghi Org Synth Coll Vol V 645 1973.] It is very soluble in H2O and can be crystallised from Et2O. [Kfod Acta Chem Scand 10 256 1956, Beilstein 3 IV 170.]

References

Gr?sland et al. (1985), The tyrosyl free radical in ribonucleotide reductase; Health Perspect., 64 139 Yarbro (1992), Mechanism of action of hydroxyurea; Oncol., 3 (Suppl 9) 1 Singh and Xu (2016), The Cell Killing Mechanisms of Hydroxyurea; Genes (Basel), 7 99 Campbell et al. (2021), Temporal modulation of the NF-kB Re1A network in response to different types of DNA damage; J., 478 533 Baliga et al. (2000), Mechanism for fetal hemoglobin induction by hydroxyurea in sickle cell erythroid progenitors; J. Hematol., 65 227 Kwak et al. (2021), Hydroxyurea selection for enhancement of homology-directed targets integration of transgenes in CHO cells; Biotechnol, 62 26