Elimination of Cocaine by Pregnant Sheep following Single or Multiple Exposures

To test the hypothesis that chronic exposure to cocaine would alter drug elimination in pregnant and fetal sheep compared to a single exposure, we administered intravenous cocaine HCl to 8 pregnant sheep daily as a bolus, followed by a 2-h infusion begin- ning at gestational age 75 days. Eight additional animals received an equivalent volume of saline. Three days after maternal and infusion. These changes in metabolite concentrations could not be explained by altered cocaine metabolism, but may reflect accumulation in the animal. Given that the fetus has limited metabolic pathways compared to adults, chronic exposure to cocaine in the fetus could result in greater accumulation of the drug and a corresponding change in drug clearance. Alterna- tively, repetitive exposure to cocaine in the fetus could lead to dispositional tolerance manifested by an increase in the rate of clearance. To test these possibilities, we examined the clear- ance of cocaine and benzoylecognine in maternal and fetal sheep that had been chronically exposed to cocaine, and com- pared the results with sheep receiving the drug for the first time.