Pharmacokinetics of Morphine and its Surrogates VIII: Naloxone and Naloxone Conjugate Pharmacokinetics in Dogs as a Function of Dose and as Affected by Simultaneously Administered Morphine

Abstract

Reversed-phase HPLC assays with electrochemical detection, developed to quantify naloxone, 6β-naloxol, and their hydrolyzed conjugates in biological fluids provided assay sensitivities of 10 to 20ng/mL in plasma, urine, and bile. These fluids were monitored in dogs after iv bolus administrations of 0.47 and 4.7mg/kg of naloxone. Plasma concentration-time data were well fitted by the sums of two exponentials with two sequential half-lives of 11 ± 1 (SEM) and 56 ± 3min. Pharmacokinetics were dose-independent; total and renal clearances were 1334 ± 133mL/min and 42 ± 9mL/min, respectively, with a renal clearance of 65 ± 5mL/min for the conjugate. The percentage of the dose excreted in the urine as naloxone was 4.4 ± 1.0%. There was a possible dose-dependent excretion of conjugate with 46 ± 1 and 22 ± 5% of the dose renally excreted at the high and low doses, respectively. In incomplete biliary cannulation, 13 and 18% were collected as conjugate in the bile of two bile-cannulated dogs. There was negligible biliary secretion of unchanged naloxone. Neither 6β-naloxol nor its conjugates were metabolites of naloxone in dogs. The simultaneous administration of naloxone does not reverse the dose-dependent pharmacokinetic perturbations of morphine. Morphine significantly lessened its own body, renal, and biliary clearances, as well as those of naloxone, and also lowered their apparent overall volumes of distribution. Plasma levels of naloxone and its conjugate were elevated with simultaneous morphine administration. Urinary flow rates were also greatly lessened and initial renal shut-down was implied at the higher morphine dose. Thus, the established competitive antagonistic action of naloxone on morphine does not extend to the reversal of the biological feedback effects of morphine on the metabolism and excretion of itself and simultaneously administered naloxone.