Karl Verebey

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

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, β‐naltrexol, was 87.2 ± 25.0 ng/ml at 2 hr. Twenty‐four hours after the dose the X levels of naltrexone and f3‐naltrexol declined to 2.1 ± 0.47 and 17.6 ± 5.0 ng/ml, respectively. Following chronic administration the X peak plasma levels of naltrexone and β‐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 f3‐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 β‐naltrexol in the first 24 hr. The half‐life of naltrexone and β‐naltrexol decreased slightly from the acute to the chronic 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.

Phencyclidine-induced stereotypy in rats: Effects of methadone, apomorphine, and naloxone

Phencyclidine (PCP) given to male Wistar rats produced hyperactivity and various stereotypic motor behaviors. Methadone, apomorphine, and naloxone were tested for their effects on PCP-induced stereotypy. Methadone (0.5 mg/kg) had not effect on the hyperactivity produced by PCP, but significantly attenuated PCP-induced stereotypy when given both before and after PCP. Low doses of apomorphine were equally effective as methadone in attenuating PCP-induced stereotypy. However, when naloxone was given after methadone or apomorphine to PCP-treated rats, the full PCP-induced stereotypy was again observed. Naloxone pretreatment in doses up to 20 mg/kg was not effective in antagonizing PCP-induced behavioral effects. Methadone and apomorphine antagonism of PCP-induced stereotypy may be mediated by opiate receptors. The results of this study and observations from human studies collectively suggest the possible effectiveness of opiates in treating PCP-induced and functional psychoses.

Quantitative determination of naltrexone and betanaltrexol in human plasma using electron capture detection

Abstract A gas-liquid chromatographic method is described for the determination of naltrexone and beta-naltrexol in human plasma following derivatization with pentafluoropropionic anhydride using electron capture detection. The lower sensitivity of the method for absolute standards is 5–10 pg. Following an acute 100-mg dose to a subject, peak levels of naltrexone of 15 ng/ml at 2 h and of beta-naltrexol 84 ng/ml at 4 h were observed. The levels of both compounds decreased by 24 h after the dose: naltrexone to 2.9 ng/ml and beta-naltrexol to 25 ng/ml. Following chronic administration for two weeks of 100 mg per day the peak levels of naltrexone and betanaltrexol increased to 26.9 and 131 ng/ml at 2 h, respectively, but by 24 h both compounds were at levels similar to those following a single dose. Thus no accumulation of either drug or metabolite in the plasma was seen following chronic naltrexone administration.

Methadone dose, plasma level, and cross-tolerance to heroin in man.

The development of cross-tolerance between methadone and heroin was studied in postaddict volunteers who had been drug-free for at least 6 weeks. Two methadone dose schedules were used; each was employed in six subjects. One schedule brought the subjects to a dose of 40 mg, while the other brought them to 80 mg of methadone a day. Subjects received injections of heroin (0.214 mg/kg) and placebo at various times before and during methadone treatment. Pupillary and subjective effects of injections were measured. Plasma levels of methadone were determined concurrently. Subjects on both treatment schedules developed an incomplete cross-tolerance to this dose of heroin. As the dose and plasma level of methadone increased with time, the cross-tolerance to all heroin effects increased. Plasma levels did not affect the development of cross-tolerance independently of methadone dose. The most important contribution to the cross-tolerance to pupillary effects was made by the duration of methadone treatment. Furthermore, the cross-tolerance to the subjective effects of heroin developed earlier than that to the pupil effect.

Endorphins and Mental Disease

It was recognized many years ago that endogenous regulation of physiological processes is often performed by chemicals synthesized in the organism. Many of the chemicals are peptide hormones. A certain portion of each peptide chain has a specific amino acid sequence representing the “keys” that turn on or off the “locks” of the receptors, which regulate specific physiological functions. Recently, it has been discovered that a very-well-studied group of drugs, the opioids, have endogenous peptide analogs called the endorphins. Various sizes have been found, the smallest being the pentapeptide enkephalins. Somewhat larger are the dynorphins, containing up to 21 amino acids. The largest oligopeptides (e.g., s-endorphin) contain 31 amino acids. One characteristic common to other endorphins is that somewhere in the polypeptide molecule, the amino acid sequence of Met-enkephalin is present. This indicates that the active principle for opioid activity is coded by 4 or 5 amino acids in a specific sequence.