Effects of labetalol on cocaine pharmacokinetics in neonatal piglets.
Developmental exposure to cocaine can produce adverse neurobehavioral and cardiovascular effects. Few animal models of human neonatal exposure have been established. A pharmacokinetic study was therefore conducted to characterize the disposition of cocaine and a major metabolite benzoylecgonine (BE) using piglets as an animal model. Eight piglets (postnatal days 8-9) were instrumented with a jugular cannula for drug administration and blood sampling. One group of subjects (controls) received 6.0 mg/kg of cocaine-HCl (i.v.) and blood samples were drawn over 0-24 h. In another group (labetalol), 0.25 mg/kg labetalol-HCl was coadministered 15 min following cocaine dosing. Plasma levels of cocaine and BE were determined using GC-MS methods. Pharmacokinetics were evaluated by using a model-independent approach and compartmental modeling. For controls model-independent results were as follows: AUC = 148.9 +/- 9.0 mg/l x min, systemic clearance = 0.041 +/- 0.003 liters/min/kg, volume of distribution = 1.543 +/- 0.470 liters/kg, and t1/2 beta = 29.4 +/- 6.8 min. Cocaine followed two-compartment model kinetics with distribution and elimination half-lives of 0.3 +/- 0.1 and 58.0 +/- 18.0 min, respectively. Labetalol significantly decreased systemic clearance to 0.029 +/- 0.004 liters/min/kg. BE kinetics revealed a elimination half-life of 230.0 +/- 83.2 min. The results demonstrate a rapid distribution and metabolism of cocaine to BE followed by a prolonged elimination phase which is extended by labetalol treatment.
Scalzo
F M
FM
Arkansas Children's Hospital Research Center, University of Arkansas for Medical Sciences, Little Rock 72202.
Primozic
S
S
Burge
L J
LJ
Badger
T M
TM
Creer
M H
MH
Nehus
C
C
Karba
R
R
D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism*; D003042:Cocaine / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000633:toxicity; D004353:Drug Evaluation, Preclinical; D007741:Labetalol / Q000494:pharmacology*; D008954:Models, Biological; D013552:Swine
C005618:benzoylecgonine; D003042:Cocaine; D007741:Labetalol