Ovine fetal-placental cocaine pharmacokinetics during continuous cocaine infusion.
OBJECTIVE
To investigate fetal-placental cocaine clearance, and to determine the fetal catecholamine and cardiovascular responses 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. Fetuses 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 plasma 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 pharmacokinetic process. Fetal plasma concentration of benzoylecgonine, a principle cocaine metabolite, increased throughout the study to approximately 25% above cocaine levels by 90 minutes. There were significant increases in fetal heart rate (from 169 +/- 11 to 242 +/- 36 beats per minute), mean blood pressure (from 53 +/- 4 to 63 +/- 5 mmHg), and systolic 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.


CONCLUSIONS
Fetal-placental clearance of cocaine is a rapid, first-order pharmacokinetic process. During prolonged cocaine exposure, plasma benzoylecgonine concentrations accumulate significantly. Significant catecholamine and cardiovascular changes are seen in fetal sheep with a continuous infusion of cocaine at 0.2 mg/kg/minute or greater.
Downs
T
T
Department of Obstetrics and Gynecology, Harbor-UCLA Perinatal Research Laboratories, Torrance 90502, USA.
Padbury
J
J
Blount
L
L
Kashiwai
K
K
Chan
K
K
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D002245:Carbon Dioxide / Q000097:blood; D003042:Cocaine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004837:Epinephrine / Q000097:blood; D005260:Female; D005312:Fetal Blood; D005333:Fetus / Q000187:drug effects*; D006340:Heart Rate, Fetal / Q000187:drug effects*; D007262:Infusions, Intravenous; D008431:Maternal-Fetal Exchange; D008657:Metabolic Clearance Rate; D009638:Norepinephrine / Q000097:blood; D010100:Oxygen / Q000097:blood; D010313:Partial Pressure; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D012756:Sheep
D002245:Carbon Dioxide; C005618:benzoylecgonine; D003042:Cocaine; D010100:Oxygen; D009638:Norepinephrine; D004837:Epinephrine