Pharmacokinetics and pharmacodynamics of subcutaneous naltrexone pellets in the rat

Subcutaneous implantation of naltrexone pellets is a standard method of producing chronic blockade of opioid receptors. In the present experiments, rats were treated with two, 30-mg naltrexone pellets and the pharmacokinetics and pharmacodynamics examined. This dosing method produced high plasma naltrexone levels (350 ng/ml) by 1 hr which declined over an implant period of 192 hr (24 ng/ml). Approximately 40% of the systemically available naltrexone (15.6 mg) was released in the first 24 hr. A total of 39.8 mg was released over the 192-hr implantation period. At 192 hr after implantation, naltrexone produced a greater than 50-fold shift to the right in the dose-response curve for morphine analgesia relative to placebo-implanted controls. When naltrexone pellets were removed at 192 hr after implantation, morphine analgesia (10 mg/kg) returned with a time course that was inversely related to the elimination of naltrexone. Pharmacokinetic analysis indicated that naltrexone has a terminal elimination half-life of 4.6 hr. Probit analysis revealed a linear plasma level-response relationship for naltrexone antagonism of morphine analgesia with a plasma ED50 of 2.1 ng/ml when plasma morphine levels average 1126 ng/ml. In the rat, s.c. naltrexone pellets are a dosage form that provides a rapid release of systemic drug. The systemic availability of naltrexone continues for at least 192 hr after implantation. The high potency of naltrexone permits continued antagonism of morphine even when the systemic availability of naltrexone from the pellets has greatly diminished.