Transfer of phenylbutazone and ivermectin from dam to offspring during the perinatal period in a Holstein cow model

Abstract

When a pregnant or breast feeding woman requires treatment for a disease condition during the perinatal period, a major concern is whether drug therapy will result in a potentially harmful drug exposure to her offspring. To obtain approval to legally market a drug, a drug manufacturer must prove to the Food and Drug Administration that the drug is safe and effective for its intended use. Proof of safety for use in pregnant or breast feeding mothers is currently not required. Therefore, information on drug transfer and offspring exposure needed to evaluate the potential risk associated with a therapeutic option is generally not available. The pregnant Holstein cow and her newborn calf was tested as an animal model that may be used to study in utero and lactational drug transfer and offspring exposure. Two drugs used in human medicine and veterinary medicine, phenylbutazone and ivermectin were tested in the model. Prior to parturition, pregnant cows were dosed orally to steady-state with phenylbutazone at 5 mg/kg/day or given a single subcutaneous injection of 200 mcg ivermectin/kg bw. The level of drug transfer to calves exposed in utero, in utero combined with lactational exposure, and lactational exposure only, were measured from days 1 through 7 postpartum. At birth the plasma level in phenylbutazone-exposed calves was approximately 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. For both drugs, rapid accumulation of the drug in calf plasma occurred with lactational exposure during the first week of life to a mean daily dose of 2 mcg ivermectin/kg bw or 0.09 mg phenylbutazone/kg bw/day. The accumulation observed in the newborn calf is attributed to the lipid solubility and long elimination half-lives of these drugs. Thus the results showed that drug transfer and offspring exposure could be studied in the cow-calf model. The results highlight the importance of considering not only the dose but also physicochemical characteristics and pharmacokinetics when evaluating the safety of a newborn's exposure to a drug in breast milk.