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.

No abstract

The biologic disposition of methadone in acute and during chronic administration was studied in 12 human volunteers. In the acute study a biexponential methadone plasma level decay was observed. The acute primary half-life (t1/2) of 14.3 hr in combination with the acute secondary t1/2 of 54.8 hr were longer than the single exponential chronic t1/2 of 22.2 hr determined in the same subjects. The urinary and fecal excretion of methadone and its mono-N-demethylated metabolite increased from 22.2% in the acute to 62.0% in the chronic phase of the study. The urinary metabolite 1 to methadone ratio tripled from the acute to the chronic phase. The pupillary effects of methadone monitored throughout 24 hr were nearly the same in magnitude in the acute and the chronic studies, whereas the plasma levels increased 3- to 8-fold following chronic methadone administration. These findings suggest that both dispositional and pharmacologic tolerance are involved in the development of tolerance following chronic administration of methadone.

Nineteen healthy volunteer subjects who regularly administered cocaine to themselves were given placebo and 10 and 25 milligrams of cocaine hydrochloride intravenously and intranasally. A dose of 100 milligrams of cocaine was administered only by the intranasal route. By this route 10 milligrams of cocaine produced no changes different from placebo, and 25 milligrams of cocaine produced physiologic changes only in systolic blood pressure. The 100-milligram dose given intranasally and all of the doses given intravenously produced significant dose-related physiologic and subjective responses.