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Mechanism of Action
The precise mechanism by which hydroxyurea produces its antineoplastic effects cannot, at present, be described. However, the reports of various studies in tissue culture in rats and humans lend support to the hypothesis that hydroxyurea causes an immediate inhibition of DNA synthesis by acting as a ribonucleotide reductase inhibitor, without interfering with the synthesis of ribonucleic acid or of protein. This hypothesis explains why, under certain conditions, hydroxyurea may induce teratogenic effects.
Three mechanisms of action have been postulated for the increased effectiveness of concomitant use of hydroxyurea therapy with irradiation on squamous cell (epidermoid) carcinomas of the head and neck. In vitro studies utilizing Chinese hamster cells suggest that hydroxyurea (1) is lethal to normally radioresistant S-stage cells, and (2) holds other cells of the cell cycle in the G1 or pre-DNA synthesis stage where they are most susceptible to the effects of irradiation. The third mechanism of action has been theorized on the basis of in vitro studies of HeLa cells: it appears that hydroxyurea, by inhibition of DNA synthesis, hinders the normal repair process of cells damaged but not killed by irradiation, thereby decreasing their survival rate; RNA and protein syntheses have shown no alteration.
Hydroxyurea is readily absorbed after oral administration. Peak plasma levels are reached in 1 to 4 hours after an oral dose. With increasing doses, disproportionately greater mean peak plasma concentrations and AUCs are observed.
There are no data on the effect of food on the absorption of hydroxyurea.
Hydroxyurea distributes rapidly and widely in the body with an estimated volume of distribution approximating total body water.
Plasma to ascites fluid ratios range from 2:1 to 7.5:1. Hydroxyurea concentrates in leukocytes and erythrocytes.
Up to 60% of an oral dose undergoes conversion through metabolic pathways that are not fully characterized. One pathway is probably saturable hepatic metabolism. Another minor pathway may be degradation by urease found in intestinal bacteria. Acetohydroxamic acid was found in the serum of three leukemic patients receiving hydroxyurea and may be formed from hydroxylamine resulting from action of urease on hydroxyurea.
Excretion of hydroxyurea in humans is likely a linear first-order renal process.
Geriatric, Gender, Race
No information is available regarding pharmacokinetic differences due to age, gender, or race.
No pharmacokinetic data are available in pediatric patients treated with hydroxyurea.
As renal excretion is a pathway of elimination, consideration should be given to decreasing the dosage of hydroxyurea in patients with renal impairment. In adult patients with sickle cell disease, an open-label, non-randomized, single-dose, multicenter study was conducted to assess the influence of renal function on the pharmacokinetics of hydroxyurea. Patients in the study with normal renal function (creatinine clearance [CrCl] > 80 mL/min), mild (CrCl 50-80 mL/min), moderate (CrCl = 30- < 50 mL/min), or severe ( < 30 mL/min) renal impairment received hydroxyurea as a single oral dose of 15 mg/kg, achieved by using combinations of the 200 mg, 300 mg, or 400 mg capsules. Patients with end-stage renal disease (ESRD) received two doses of 15 mg/kg separated by 7 days, the first was given following a 4-hour hemodialysis session, the second prior to hemodialysis. In this study, the mean exposure (AUC) in patients whose creatinine clearance was < 60 mL/min (or ESRD) was approximately 64% higher than in patients with normal renal function. The results suggest that the initial dose of hydroxyurea should be reduced when used to treat patients with renal impairment. (See PRECAUTIONS and DOSAGE AND ADMINISTRATION.) Close monitoring of hematologic parameters is advised in these patients.
There are no data that support specific guidance for dosage adjustment in patients with hepatic impairment. Close monitoring of hematologic parameters is advised in these patients.
There are no data on concomitant use of hydroxyurea with other drugs in humans.
Animal Pharmacology and Toxicology
The oral LD50 of hydroxyurea is 7330 mg/kg in mice and 5780 mg/kg in rats, given as a single dose.
In subacute and chronic toxicity studies in the rat, the most consistent pathological findings were an apparent dose-related mild to moderate bone marrow hypoplasia as well as pulmonary congestion and mottling of the lungs. At the highest dosage levels (1260 mg/kg/day for 37 days, then 2520 mg/kg/day for 40 days), testicular atrophy with absence of spermatogenesis occurred; in several animals, hepatic cell damage with fatty metamorphosis was noted. In the dog, mild to marked bone marrow depression was a consistent finding except at the lower dosage levels. Additionally, at the higher dose levels (140 to 420 mg or 140 to 1260 mg/kg/week given 3 or 7 days weekly for 12 weeks), growth retardation, slightly increased blood glucose values, and hemosiderosis of the liver or spleen were found; reversible spermatogenic arrest was noted. In the monkey, bone marrow depression, lymphoid atrophy of the spleen, and degenerative changes in the epithelium of the small and large intestines were found. At the higher, often lethal, doses (400 to 800 mg/kg/day for 7 to 15 days), hemorrhage and congestion were found in the lungs, brain, and urinary tract. Cardiovascular effects (changes in heart rate, blood pressure, orthostatic hypotension, EKG changes) and hematological changes (slight hemolysis, slight methemoglobinemia) were observed in some species of laboratory animals at doses exceeding clinical levels.
Last reviewed on RxList: 6/23/2010
This monograph has been modified to include the generic and brand name in many instances.
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