Comparative distribution and embryotoxicity of hydroxyurea in pregnant rats and rhesus monkeys

Abstract

Hydroxyurea was given to pregnant rhesus monkeys and pregnant rats in regimens adjusted to produce similar degrees of teratogenicity, for the purpose of comparing the distribution of the drug in the females and their embryos. According, in rats 137 mg/kg/day ip on days 9-12 resulted in a drug half-life in maternal plasma of about 15 min and in embryos about 85 min, after the last injection; and in monkeys 100 mg/kg/days iv on days 23-32 resulted in drug half-life in maternal plasma estimated to be 120 min and in embryos 265 min, after the last injection. Using as a baseline of biological effects the minimal concentration known to inhibit DNA synthesis in rat embryos and cancer cells, namely 10(-4) M, it was calculated that the rat embryos in the present study were exposed to this level or more for approximately 12 h whereas the monkey embryos were exposed for approximately 100 h. Although the teratogenic effects were not identical in the two species, these data are interpreted to mean that rat embryos are teratogenically much more sensitive to hydroxyurea than monkey embryos. These observations have important implications in the selection of appropriate species for tests to estimate human teratogenic risks. The rat, which is currently the most widely used animal for such tests, displays sizeable differences from rhesue monkeys, which is one of the animals thought to be most like man in teratogenic susceptibility.

Hydroxycarbamide: a user’s guide for chronic myeloproliferative disorders

“…Hydroxycarbamide is not indicated for women during reproductive years because it crosses the placenta, and experimental evidence suggests that it may be teratogenic [48,88,89]. However, there are no published reports of such effects in humans.…”

Evaluation and Treatment of the Human Immunodeficiency Virus-1—Exposed Infant

“…56 Hydroxyurea is another antiretroviral agent for which teratogenicity has been observed in several animal species, but information in human pregnancies is limited. [69][70][71] Other medications given to the mother for complications associated with HIV-1 infection also can be teratogenic. For example, fluconazole has been associated with congenital craniofacial, skeletal, and cardiac anomalies in infants, but the strength of this association remains controversial.…”

Interagency Regulatory Liaison Group Workshop on Reproductive Toxicity Risk Assessment

“…(g) Knowledge of pharmacokinetic parameters in two test species facilitates the selection of dosage regimens for the investigation of species susceptibility at equivalent exposure (36,79,80).…”

“…Pharmacokinetics can determine the dosage levels to be employed to maintain equivalent concentrations of the parent compound in the two species. With such an approach the relative sensitivity of the species to the toxicant can be assessed (36,79,80). If the reproductive toxicity is due to a metabolite, pharmacokinetic data can be used to determine which species are likely to be susceptible based on the ability to form the toxic metabolite (84).…”