Naltrexone: Disposition, metabolism, and effects after acute and chronic dosing

Abstract

The disposition of naltrexone during acute and chronic administration of 100-mg oral dose was studied in 4 subjects. Following an acute dose the mean (X) peak naltrexone plasma level was 43.6 +/- 29.9 ng/ml at 1 hr and for the major biotransformation product, beta-naltrexol, was 87.2 +/- 25.0 ng/ml at 2 hr. Twenty-four hours after the dose the X levels of naltrexone and beta-naltrexol declined to 2.1 +/- 0.47 and 17.6 +/- 5.0 ng/ml, respectively. Following chronic administration and X peak plasma levels of naltrexone and beta-naltrexol rose to 46.4 +/- 18.5 and 158.4 +/- 89.9 ng/ml at 1 hr, but by 24 hr both compounds declined to levels of the same order as in the acute state at 24 hr. Plasma levels of naltrexone and beta-naltrexol measured 24 hr after the daily doses of naltrexone throughout the study indicated that steady-state equilibrium was rapidly attained and that there was no accumulation of naltrexone and beta naltrexol in the plasma after chronic treatment on 100 mg oral doses. Biexponential kinetics were observed for naltrexone and beta-naltrexol in the first 24 hr. The half-life of naltrexone and beta-naltrexol decreased slightly from the acute to thechronic study from 10.3 +/- 3.3 to 9.7 +/- 1.1 hr and from 12.7 +/- 2.6 to 11.4 +/- 2.0 hr. The plasma levels of naltrexone declined slowly from 24 through 72 hr from 2.4 to 1.7 ng/ml, with an apparent half-life of 96 hr. The renal clearance data indicate that naltrexone is partially reabsorbed while beta naltrexol is actively secreted by the kidney. During acute and chronic naltrexone administration the mean fecal excretion was 2.1% and 3.6% while urinary excretion was 38% and 70% of the dose in a 24-hr period. Opiate antagonism to 25 mg heroin challenges was nearly complete through 48 hr after naltrexone. At 72 hr the objective responses reappeared to a greater extent than the subjective ones. Correlation coefficient (r) between naltrexone plasma levels and opiate antagonism was 0.91 and between individual half-life of naltrexone and opiate antagonism it was 0.99.

Hypothalamic-Pituitary-Adrenocortical (HPA) Axis Response and Biotransformation of Oral Naltrexone Preliminary Examination of Relationship to Family History of Alcoholism

“…Levels of peak 6-␤-naltrexol were approximately 10 times greater than naltrexone, which has been reported in past studies (Cone et al 1974;King et al 1997b;Verebey et al 1976;Wall et al 1981). Naltrexone levels in blood peaked at 60-120 min, and 6-␤-naltrexol levels peaked 120 min after administration.…”

Depot naltrexone: long-lasting antagonism of the effects of heroin in humans

“…An early study conducted by Vereby and colleagues (Vereby et al 1976) showed that 100 mg oral naltrexone did not completely antagonize the effects of 25 mg IV heroin when plasma levels of naltrexone fell below approximately 2 ng/ml. In contrast, Navaratnam and colleagues (Navaratnam et al 1994) showed that after discontinuation of day 1-day 3-day 5 dosing with 100-100-150 mg oral naltrexone, antagonism of the effects of 25 mg IV heroin continued to occur when plasma levels of naltrexone were negligible.…”

In vivo evaluation of a transdermal codrug of 6-β-naltrexol linked to hydroxybupropion in hairless guinea pigs

“…Compared with naloxone, NTX has a longer duration of action, allowing for once daily dosing. This long duration of action is largely considered to be due, in part, to its major metabolite, 6-β-naltrexol (Verebey et al, 1976;Volpicelli, 1995). In humans, NTX undergoes extensive first-pass metabolism with an oral bioavailability of 5-40% and the primary metabolite, 6-β-naltrexol, is formed via reduction of the 6-keto group in NTX.…”

“…Data from a study of alcoholics showed a significant negative correlation between high plasma levels of 6-β-naltrexol and a lower reported number of drinks per month (McCaul et al, 2000). 6-β-Naltrexol is expected to have a more predictable biotransformation profile and may be useful in providing a more precise control over dosing compared to the variability experienced with NTX oral dosing (Ferrari et al, 1998;McCaul et al, 2000;Verebey et al, 1976). Also, 6-β-naltrexol may be better tolerated than NTX in recovering opioid addicts, due to its neutral antagonist profile and potential decreased withdrawal effects (Raehal et al, 2005).…”