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Ovine Fetal-Placental Cocaine Pharmacokinetics During Continuous Cocaine Infusion

James Padbury, MD

Leslie Blount, BS

Kent Kashiwai, BS

Kenneth Chan, MD

Department of Obstetrics and Gynecology, Harbor-UCLA Perinatal Research Laboratories, Torrance, California, USA

Objective: To investigate fetal-placental cocaine clearance, and to determine the fetal catecholamine and cardiovascular response to continuous intravenous cocaine infusion in fetal sheep.

Methods: Eleven pregnant ewes and their fetuses (127 ± 2 days' gestation; term 150 days) were chronically instrumented. Fetrues received intravenous cocaine at 0.05, 0.1, or 0.2 mg/kg/minute. Fetal cardiovascular and hematologic measurements were made before and serially for 90 minutes after initiation of the cocaine infusion.

Results: Steady-state fetal cocaine concentrations were observed by 15 minutes of infusion and averaged 136 ± 11, 318 ± 65, and 610 ± 36 ng/mL, respectively, at each dose. Fetal-placental cocaine clearance rate was independent of dose (337 ± 39 mL/kg/minute), indicating that it is a first-order pharmacokinectic process. Fetal plasma concentration of benzoylecognine, a principle cocaine metabolite, increased throughout the study to approximately 25% above cocaine levels by 90 minutes. There were significant increase in fetal heart rate (from 169 ± 11 to 242 ± 36 beats per minute), mean blood pressure (from 53 ± 4 to 63 ± 5 mmHg), and sytolic blood pressure (from 68 ± 2 to 80 ± 5 mmHg), with a corresponding increase in catecholamine levels seen in the fetuses infused with 0.2 mg/kg/minute. These changes were not seen in the fetuses given lower doses of cocaine.

Conclusion: Fetal-placental clearnace of cocaine is a rapid, first-order pharmacokinetic process. During prolonged cocaine exposure, plasma benzoylecgonine concentrations accumulate significantlay. Significant catecholamine and cardiovascular changes are seen in fetal sheep with a continuous infusion of cocaine at 0.2 mg/kg/minute or greater.

Key Words: Ovine • cocaine • fetus • clearnace

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