Toxicology Brief: Hydroxyurea toxicosis in dogs and cats

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Aug 01, 2011


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Hydroxyurea is a prescription-only antineoplastic drug—available as 200-, 300-, 400-, or 500-mg capsules—given orally to dogs, cats, and people.1,2 In people, it is given to treat melanoma, resistant chronic myelocytic leukemia, and carcinoma of the ovary and to control primary squamous cell carcinoma of the head and neck. Sometimes, it is also used as an adjunctive therapy for patients with HIV infection or AIDS, psoriasis, or sickle cell anemia.3,4 In dogs and cats, it is indicated for treating polycythemia vera, mastocytomas, and leukemias.2

Recommended oral dosages to treat various conditions (polycythemia vera, chronic myelogenous leukemia) in dogs include 50 mg/kg three times a week, 30 mg/kg once daily for one week and then 15 mg/kg/day until remission, or 20 to 25 mg/kg twice daily, tapering off to every other day once the hematocrit is < 60%.2 In cats, the oral dosage is 25 mg/kg three times a week or 30 mg/kg once daily for one week, tapering off to 15 mg/kg once daily until remission and then to the lowest effective frequency as determined by monitoring the hematocrit.2

TOXICOKINETICS

Hydroxyurea is well-absorbed orally, with the peak plasma concentration seen within one to four hours after administration. The drug readily crosses the blood-brain barrier and is well-distributed in other body tissues. Protein binding is between 75% and 80%. About 50% of the drug is metabolized in the liver, and the remaining 50% (range = 36% to 62%) is eliminated through the kidneys as unchanged drug and as urea. The reported elimination half-life is two to four and a half hours.1,4

The exact mechanism of action of hydroxyurea is not known, but it appears to interfere with DNA synthesis without interfering with RNA or protein synthesis. It is known to inhibit the conversion of DNA bases by blocking the enzyme ribonucleoside diphosphate reductase, possibly resulting in direct damage to the DNA. Myelosuppression seems to occur as a result of inhibition of DNA synthesis.1,3,4

TOXICITY

Hydroxyurea appears to be well-tolerated in animals, with low acute oral toxicity. The oral LD50 in mice and rats is 7,330 and 5,760 mg/kg, respectively.1 Methemoglobinemia can occur in cats given doses exceeding 500 mg.2

Adverse effects of long-term hydroxyurea use in people include gastrointestinal complications (nausea, vomiting, diarrhea, constipation, mucositis); myelosuppression (leukopenia, thrombocytopenia, anemia); cutaneous effects (rashes, ulcers, melanonychia [black pigmentation of nails]); hepatitis, occasionally; and reversible renal damage.3,4

Onychomadesis (nail shedding) involving several claws on all feet in two dogs receiving long-term hydroxyurea treatment has been described.5 Both dogs recovered, one after the cessation of treatment and the other after the dosage was reduced.5 Acute toxicosis characterized by the development of methemoglobinemia, moderate thrombocytopenia, and mild delayed neutropenia has been reported in one dog that had possibly ingested 200 to 300 mg/kg of hydroxyurea belonging to the owner. The dog made a full recovery with aggressive supportive treatment.1

APCC DATA

A review of the ASPCA Animal Poison Control Center (APCC) toxicology database from 2003 to 2009 found 16 hydroxyurea cases involving 13 dogs and three cats.6 These cases involved exposure to one agent (hydroxyurea) only and were assessed as medium-suspect (history of exposure, some clinical signs consistent with hydroxyurea toxicosis) or high-suspect cases (history of exposure, clinical signs consistent with hydroxyurea toxicosis).