Etrophine in man. II. Detectability in urine by common screening methods.

A single highly euphorogenic dose of etorphine, 100 mug, was administered subcutaneously to 7 nontolerant subjects, and all urine samples were collected for 1 day prior to and 3 days following drug administration. Samples were analyzed for the presence of opiates by radioimmunoassay (Abuscreen) and homogeneous enzyme immunoassay (EMIT), with cutoffs for "ositives" of 40 and 500 ng/ml, respectively. Samples were analyzed for etorphine by thin-layer chromatography (TLC) with iodoplatinate preceded by XAD-2 resin extraction (sensitivity = 0.2 mug etorphine/ml of urine) and by gas-liquid chromatography (GLC) preceded by organic solvent extraction and trimethylsilyl derivatization (sensitivity = 0.1 mug etorphine/ml of urine). The last pre-drug and first two post-drug samples were also analyzed after acid hydrolysis by TLC and after glucuronidase hydrolysis by TLC and GLC. No sample gave a "positive" opiate result in either immunoassay, and no etorphine was detected in the TLC and GLC analyses of any urine sample. Thus, it is unlikely that the abuse of etorphine could be diagnosed by urinalysis using the common screening methods of radioimmunoassay, EMIT, TLC preceded by XAD-2 resin extraction, or GLC preceded by organic solvent extraction and trimethylsilyl derivatization.

The pharmacokinetics of pentazocine and tripelennamine.

The pharmacokinetics of single and combined doses of pentazocine HCl (40 and 80 mg) and tripelennamine HCl (50 and 100 mg) were studied in six healthy drug abusers. After intramuscular administration of 40 or 80 mg pentazocine alone, mean peak plasma concentrations at 15 minutes were 102 and 227 ng/ml, respectively, and mean plasma t1/2 values were 4.6 and 5.3 hours, respectively. After intramuscular administration of 50 or 100 mg tripelennamine, mean plasma concentrations at 30 minutes were 105 and 194 ng/ml, respectively, and mean plasma t1/2 values were 2.9 and 4.4 hours, respectively. After concurrent administration of pentazocine with tripelennamine, plasma pentazocine and tripelennamine concentrations at all time points were not significantly different from those when pentazocine or tripelennamine was administered alone. Coadministration of pentazocine and tripelennamine had no effect on the distribution, elimination, and clearance of either pentazocine or tripelennamine. In conclusion, there did not appear to be a clinically significant metabolic interaction between pentazocine and tripelennamine.

Diazepam and methadone blood levels following concurrent administration of diazepam and methadone.

Results of a previous study indicated that the opioid effects of methadone were enhanced by the concurrent administration of diazepam in methadone-maintained subjects. To determine whether a pharmacokinetic interaction might account for this methadone-diazepam interaction, the plasma levels of methadone, diazepam and diazepam metabolites were determined in blood samples collected during that study. Five adult male patients on methadone maintenance (50-60 mg/day) were administrated single doses of placebo, diazepam (20 and 40 mg), methadone (100%, 150% and 200% of the maintenance dose), and four diazepam-methadone dose combinations (20 and 40 mg diazepam in combination with 100% and 150% of the maintenance dose). The results showed that the concurrent administration of methadone and diazepam did not significantly change the time-course or areas under the plasma concentration-time curve of methadone, diazepam or N-desmethyl-diazepam compared to the levels following the administration of either drug alone. Thus, plasma drug level analysis does not indicate a pharmacokinetic interaction between diazepam and methadone.

Possible effects of normetabolites on the subjective and reinforcing characteristics of opioids in animals and man.

When an opioid capable of forming active metabolites is administered, the total pharmacology is the result of interactions of the opioid and such metabolites, especially normetabolites. Normetabolites may affect the morphine-like characteristics of certain opioids and thus influence their reinforcement in animals and man. Most opioids, when administered in single doses, are positively reinforcing in addicts. Oral administration, as compared with parenteral, facilitates the formation of normetabolites. When chronically administered, many opioids, including acetylmethadol, meperidine, morphine, codeine, propoxyphene, and levorphanol, show evidence of a longer half-life for their normetabolites. Normetabolites may have aversive characteristics and thus impair positive reinforcement of the parent drug in animals and man. For example, addicts do not like chronic oral morphine or chronic oral codeine. Conversely, methadone, the normetabolites of which are inactive, is well accepted during chronic oral administration. Drugs which inhibit N-demethylation will increase the agonist potency of opioids having inactive normetabolites (e.g., methadone) but will decrease the agonist potency of opioids having more potent normetabolites than the parent (e.g., acetylmethadol). The divergent responses of addicts to single doses of opiates as compared with chronic doses indicate that chronic addiction tests in man are needed befored relative abuse liability can be predicted.

Isolation and identification of morphine n-oxide alpha- and beta-dihydromorphines, beta- or gamma-isomorphine, and hydroxylated morphine as morphine metabolites in several mammalian species.

New morphine metabolites in the urine of guinea pigs, rats, rabbits, cats, monkeys, and humans were isolated with column chromatography, solvent extraction, and TLC and identified with TLC, GLC, and GLC-mass spectrometry. In addition to the known morphine metabolites, morphine N-oxide was isolated from the urine of guinea pigs, and alpha- and beta-dihydromorphines were isolated or detected in the urine of guinea pigs, rats, and rabbits. Monohydroxymorphine was identified tentatively in the urine of guinea pigs, rats, rabbits, and cats. Dihydroxymorphine was identified tentatively in the urine of guinea pigs, rats, and possibly, rabbits. Finally, beta- or gamma-isomorphine was identified tentatively in the urine of guinea pigs. The newly described morphine metabolites may be involved in some long lasting pharmacological effects of morphine.

Isolation and identification of morphine 3- and 6-glucuronides, morphine 3,6-diglucuronide, morphine 3-ethereal sulfate, normorphine, and normorphine 6-glucuronide as morphine metabolites in humans.

Morphine metabolites were isolated with column chromatography on a resin and neutral aluminum oxide and TLC from the urine of morphine-dependent subjects maintained on morphine sulfate at a dose of 240 mg/day. These metabolites were characterized as morphine 3-glucuronide, morphine 6-glucuronide, morphine 3,6-diglucuronide, morphine 3-ethereal sulfate, normorphine, normorphine 6-glucuronide, and, possibly, normorphine 3-glucuronide by free phenol and glucuronide tests, enzymatic hydrolysis, GLC, TLC, UV spectroscopy, and GLC--mass spectrometry.

Biosynthesis, isolation, and identification of 6-beta-hydroxynaltrexone, a major human metabolite of naltrexone.

Chemical reduction of naltrexone is described in an attempt to synthesize 6-beta-hydroxynaltrexone. Only the epimer, 6-alpha-hydroxynaltrexone, was produced. Pilot metabolic studies on naltrexone in the dog, rat, and guinea pig were made to determine which animal produced the greatest amount of 6-beta-hydroxynaltrexone. The guinea pig was selected and used to produce the metabolite. Isolation and purification methods are described, and spectral data are presented for structural confirmation of the metabolite.

Identification of diacetylmorphine metabolites in humans.

With the techniques of column chromatography, TLC, and GLC, morphine, 6-acetylmorphine, normorphine, morphine 3-glucuronide, 6-acetylmorphine 3-glucuronide, and normorphine glucuronide were identified as metabolites of diacetylmorphine (heroin) in the urine of humans administered 10 mg iv/70 kg body weight.

Urinary excretion of hydromorphone and metabolites in humans, rats, dogs, guinea pigs, and rabbits.

Hydromorphone was administered as a single dose to humans, rats, dogs, guinea pigs, and rabbits, and timed urinary collections were made. GLC-mass spectrometric and GLC analyses of the samples revealed the presence of the parent compound and both 6-hydroxy epimers as metabolites in the urine of all species. Free or conjugated parent drug predominated, while levels of free or conjugated 6beta-hydroxy metabolite were higher than or equal to those of the 6alpha-form. The time courses of excretion of drug and metabolites were similar for all species, with the major portion being excreted in the first 24 hr. Generally, free and conjugated drug were undetectable in human urine after 8 and 48 hr, respectively.

Stability of the 6,14-endo-ethanotetrahydrooripavine analgesics: acid-catalyzed rearrangement of buprenorphine.

Buprenorphine (I), a member of the 6,14-endo-ethanotetrahydrooripavine series of analgesics, undergoes an acid-catalyzed rearrangement reaction when exposed to acid and heat. The product was shown by 1H-NMR and GC-MS to have undergone overall elimination of a molecule of methanol with concurrent formation of a tetrahydrofuran ring at C(6)-C(7) of I. Short-term stability studies across a wide range of pH and temperature conditions indicate that I is stable in aqueous solution at pH greater than 3 for 24 h at 36-38 degrees C. Under the more extreme conditions of the autoclave, significant loss of I occurred. Long-term stability studies (10 weeks) of I in aqueous solution (pH 1 and pH 5) at 0-4 degrees C and 26-28 degrees C indicate only minor conversion (4%) to the rearrangement product. Eight other 6,14-endo-ethanotetrahydrooripavine derivatives were subjected to extremes of acid (pH 0) and temperature (autoclave) to determine if similar rearrangement reactions occur. GC-MS indicated that hydrolysis products were produced whose spectra were consistent with the proposed rearrangement structures.

Metabolism and excretion of normorphine in dogs.

Normorphine metabolism was studied in dogs given 20 mg of normorphine hydrochloride/kg sc. Free and (onjugated normorphine excreted in the urine over 144 hr represented 32 and 32%, respectively, of the administered dose. Eighty percent of the urinary excretion of the drug occurred within 9 hr. One percent of the administered dose was excreted as free normorphine in the feces. The urine was chromatographed on a column. Evaporation of the washing and methanolic effluent yielded a residue, which was purified by crystallization from aqueous methanol. Results of UV and IR studies, elemental analysis, and determination of normorphine and glucuronic acid content established the identity of this metabolite as normorphine 3-glucuronide. Dihydronormorphine and dehydronormorphine were detected with GLC-mass spectrometry as minor metabolites.

Comparative metabolism of codeine in man, rat, dog, guinea-pig and rabbit: identification of four new metabolites.

The metabolism and excretion of codeine and its metabolites in untreated urine of man, rat, dog, guinea-pig and rabbit have been examined. Metabolites were identified by gas chromatography mass spectrometry operated in the chemical ionization mode (methane). Concentrations of codeine and metabolites were measured by selected ion monitoring. Both codeine and norcodeine were detected in the urine of all species but a new metabolite, hydrocodone, was found only in the urine from man, guinea-pig and dog. Additional metabolites (presumably resulting from the metabolism of hydrocodone) were also detected in man and guinea-pig. Overall recoveries of drug and metabolites from untreated urine were low for all species.