Effects of Labetalol on Cocaine Pharmacokinetics in Neonatal Piglets

Abstract

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/1 X min, systemic clearance = 0.041 ± 0.003 liters/min/kg, volume of distribution = 1.543 ± 0.470 liters/kg, and t ½β = 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.

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

“…Similarly, in the present study, estimates of T 1/2α were < 1 min for all dose groups with sampling begun immediately after termination of injection. When initial blood samples are drawn, arterially, prior to 1 min after injection, estimates of T 1/2α approximate 1 min or less [pigs (61); rat (5,67), calculated; sheep (10), calculated]. With initial blood samples drawn between 1 and 5 min after bolus injection, estimates of T 1/2α approximate 1-3 min [guinea pig (59), calculated; dog (72); rat (42)].…”

Prenatal cocaine alters normoxic sleep-wake and diaphragmatic EMG patterns in piglets

“…3). Inasmuch as the reported pharmacokinetics of cocaine in piglets are comparable to those in humans, with a short elimination half-life for cocaine (0.5-1.0 h 17,18 ) and its major metabolite, benzoylecgonine (4.0 ± 1.5 h, 18 briefer than in human neonates 19 ), the drug-related findings must represent a chronic effect of cocaine on respiratory control mechanisms. Such chronicity also applies to the cocaine effects in the older piglets, in which cocaine and its metabolites would have long been eliminated.…”