Pharmacokinetics of morphine and its surrogates V: Naltrexone and naltrexone conjugate pharmacokinetics in the dog as a function of dose

Abstract

Sensitive reversed-phase HPLC assays with electrochemical detection, developed to quantify naltrexone, 6 beta-naltrexol, and their conjugates in biological fluids, provided assay sensitivities of 2-14 ng/mL in plasma, urine, and bile. Plasma, urine, and bile were monitored in dogs after bolus administrations of 0.5 and 5.0 mg/kg iv naltrexone hydrochloride. Plasma-time data showed two sequential half-lives of 5 +/- 1 (SEM) and 47 +/- 5 min. Pharmacokinetics were dose-independent; total and renal clearances were 1043 +/- 98 mL/min and 72 +/- 11 mL/min, respectively, with a similar renal clearance (85 +/- 12) for the conjugate. The percentages of the dose excreted in the urine as naltrexone and its conjugate were 7 +/- 1% and 58 +/- 3%, respectively, with the remainder being excreted in the bile as conjugates. As much as 36% was collected as conjugate in the total bile of the bile-cannulated dog. There was no biliary secretion of unchanged naltrexone. The conjugate was apparently enterohepatically recirculated. 6 beta-Naltrexol is not a metabolite of naltrexone in dogs. Within the limits of analytical detection (2 ng/mL) neither 6 beta-naltrexol nor its conjugates appeared in any monitored biological fluids when such fluids were assayed quickly after sampling.