Preliminary studies of offspring exposure to phenylbutazone and ivermectin during the perinatal period in a Holstein cow–calf model

• Published in: Toxicology and applied pharmacology 2003-03, Vol.187 (3), p.198-208
• Main Authors: Chamberlain, Pamela L, Fowler, Bruce A, Sexton, Mary J, Peggins, James O, Bredow, Jurgen von
• Format: Article
• Language: English
• Subjects: Animal modeling; Animals; Animals, Newborn - blood; Animals, Suckling - blood; Anthelmintics - administration & dosage; Anthelmintics - analysis; Anthelmintics - blood; Anthelmintics - pharmacokinetics; Anti-Inflammatory Agents, Non-Steroidal - administration & dosage; Anti-Inflammatory Agents, Non-Steroidal - analysis; Anti-Inflammatory Agents, Non-Steroidal - blood; Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics; Biological and medical sciences; Cattle; Drug toxicity and drugs side effects treatment; Embryology: invertebrates and vertebrates. Teratology; Female; Fundamental and applied biological sciences. Psychology; Half-Life; Ivermectin; Ivermectin - administration & dosage; Ivermectin - analysis; Ivermectin - blood; Ivermectin - pharmacokinetics; Lactation; Maternal-Fetal Exchange; Medical sciences; Milk - chemistry; Miscellaneous (drug allergy, mutagens, teratogens...); Models, Animal; Perinatal drug exposure; Pharmacology. Drug treatments; Phenylbutazone; Phenylbutazone - administration & dosage; Phenylbutazone - analysis; Phenylbutazone - blood; Phenylbutazone - pharmacokinetics; Pregnancy; Pregnant Holstein cows; Teratology. Teratogens
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/S0041-008X(02)00074-1

The pregnant Holstein cow and her newborn calf were evaluated as an animal model to study in utero and for lactational drug transfer and offspring exposure. A nonsteroidal antiinflammatory drug, phenylbutazone, and an antiparasitic drug, ivermectin, were tested in the model. Prior to parturition, pregnant cows were dosed orally to steady state with phenylbutazone at 4 g/day or given a single subcutaneous injection of 200 μg ivermectin/kg body wt. The level of drug transferred to calves exposed in utero, in utero combined with lactational exposure, and via lactational exposure only, was measured from days 1 through 7 postpartum. At birth the plasma level in phenylbutazone-exposed calves was approximately one-half the dam’s steady-state level. For ivermectin-exposed calves, plasma levels were at or below the limit of quantitation (0.5 ng/ml) at birth, suggesting that placental transfer of ivermectin is limited in the cow. For both drugs, rapid accumulation of the drug in calf plasma occurred with lactational exposure to a mean daily dose of 2 μg ivermectin/kg body wt or 0.1 mg phenylbutazone/kg body wt/day for the first 7 days of life. The accumulation observed in the newborn calf is attributed to the lipid solubility and long elimination half-lives of these drugs. These results demonstrate that drug transfer and offspring exposure can be studied using the cow–calf model. The data also highlight the importance of considering not only the dose but also physicochemical characteristics and pharmacokinetics of the drug in the offspring when evaluating the safety of a newborn’s exposure to a drug in breast milk.