Disposition of Cocaine in Pregnant Sheep: I. Pharmacokinetics

Abstract

Cocaine abuse by pregnant women is increasingly recognized as causing serious health consequences for mother and newborn. To assess the placental transfer and fetal effects of cocaine, we studied its pharmacokinetics following intravenous administration to the pregnant ewe and fetus. Following bolus doses of 0.5-4.0 mg/kg to ewes, cocaine appeared within 30 s in fetal circulation, with peak concentrations occurring in 4-5 min. The disappearance of cocaine in the fetal plasma paralleled that in maternal plasma, suggesting that a rapid equilibrium of cocaine occurred between maternal and fetal compartments. The mean half-life of cocaine in the fetus across doses (4.4-5.0 min) was similar to that in the ewe (4.0-5.6 min). Plasma clearance of cocaine in the ewe did not appear to vary according to dose. The fetal exposure to cocaine, as indicated by the area under the fetal plasma concentration versus curve, was a linear function of maternal cocaine dose (r = 0.96, p < 0.01). These results demonstrate rapid placental transfer of cocaine after maternal administration in an animal model and rapid metabolism by mother and fetus.

Dose-response cocaine pharmacokinetics and metabolite profile following intravenous administration and arterial sampling in unanesthetized, freely moving male rats

“…The simultaneously obtained venous samples indicated maximal values at 3-5 min after the 15-s bolus IV injection (~250 ng/ml)-values quite consonant for that dosage (~0.5 mg/kg) with the often-cited human studies (3,29,30) that provided the basis for much clinical and basic cocaine research spanning nearly two decades. The concentration vs. time profile in other mammalian species, typically obtained via arterial sampling, also displays a transient peak [guinea pig (59); dog (72); sheep (10,38,49,74); pig (37,61); monkey (58)]. The importance of considering arterial, as opposed to venous, sampling for the study of stimulant drugs of abuse such as cocaine derives from the fact that arterial concentrations are those that are delivered to the brain (33)-the putative basis for why these drugs are abused.…”

Seizures in a Fetal Lamb After Cocaine Exposure: A Case Report

“…At 134 days of gestation, with the ewe standing quietly in a cart, cocaine was infused to the fetus for 1 h (rate 0.6 mg/min, total volume 4.65 ml). This infusion gives steady-state plasma concentrations of cocaine that approximate the peak fetal cocaine concentration after administration of a 2-mg/kg dose to the pregnant ewe DeVane et al, 1991). A disruption of behavioral state occurred as previously described and was accompanied by a decrease in fetal PO, from 21 to 15 mm Hg for the duration of the experiment, returning to preinfusion partial pressures by 10 min after the infusion was stopped.…”

“…Whether these seizures were a direct effect of cocaine is not known. The short half-life of cocaine in fetal sheep (4.5 min, DeVane et al, 1991) suggests that the drug would not be present in plasma in measurable amounts 3 days after exposure. During maternal exposure to cocaine, fetuses commonly become hypoxic (Woods et al, 1987;Burchfield et al, 1991b).…”

Pharmacokinetic profile of cocaine following intravenous administration in the female rabbit

“…administration accurately mimics the human response. Rapid metabolism has also been reported in pregnant sheep (Burchfield et al, 2001;DeVane et al, 1991). Differences in circulation time and metabolic pathways among species may contribute, at least in part, to differences in drug half-life between the rat, rabbit and human (Lin, 1995).…”