Robert E. McMahon

Disposition of methadone in methadone maintenance

Six detoxified opiate addicts housed in a closed metabolic ward received methadone in stepwise increasing doses of 10, 20, 40, and 80 mg/day during 1 month. Four were given 14C‐methadone at the lowest dose and again at the highest dose. Of the subjects receiving radiomethadone, 2 excreted the major part of the radioactivity in urine and 2 about equally in urine and feces. In addition to methadone, 7 metabolites were isolated and identified in urine and 3 metabolites in feces. About 75% of the urinary and fecal radioactive metabolites were unconjugated. Urinary excretion of methadone and its major N‐monomethylated metabolite accounted for 17% to 57% of the given dose. The ratio of metabolite to parent drug increased in 5 of 6 subjects, and the urinary recovery of unchanged methadone decreased during the period. The results indicate that enhanced demethylation of methadone may occur during oral administration to man.

l-Acetylmethadol (LAM) treatment of opiate dependence: plasma and urine levels of two pharmacologically active metabolites.

The metabolic conversion of α-l-acetylmethadol (LAM) to α-l-noracetylmethadol (NAM) and α-l-dinoracetylmethanol (NNAM), has been studied in three opiate addicts being maintained on 100 mg of LAM three times weekly. Plasma levels of NAM and NNAM were established shortly after the initial dose of LAM. The plasma level of NNAM was substantially higher following repeated dosing than following the initial dose. The combined daily urinary excretion of LAM, NAM and NNAM was 6–8 times greater after repeated dosing than after the initial dose. Since NAM and NNAM, which are formed by the sequential N-demethylation of LAM are both considerably more active morphine-like agonists than is LAM itself, it is likely that the pharmacological effects of LAM are due to NAe NAM and NNAM. Variations in the rates of formation and elimination of NAM and NNAM may partially explain the variability in response seen in LAM maintenance therapy.

The fate of radiocarbon-labeled propoxyphene in rat, dog, and human.

Abstract Propoxyphene N -demethylation is the primary initial metabolic step in the rat. Ester hydrolysis also occurs. A large number of metabolic end products of propoxyphene are formed. They are mainly excreted in bile as conjugates. Metabolism in the dog appears to be less complex than in the rat. Norpropoxyphene and one other metabolite predominate, although several minor metabolites are present. The human differs from the rat and dog in that propoxyphene metabolites are eliminated primarily in urine rather than bile. Only one major metabolite, unconjugated norpropoxyphene, is present. This is readily isolated and characterized as the alkaline rearrangement product norpropoxyphene amide. Norpropoxyphene concentrations in human plasma are higher than those of propoxyphene. The half-life of norpropoxyphene is also substantially longer than that of propoxyphene.

The metabolism of nortriptyline-N-methyl-14C in rats

Abstract Nortriptyline, labeled with radiocarbon in the N-methyl group, has been prepared and its metabolism, distribution, and excretion studied in the rat. About 25% of an administered dose undergoes N-demethylation in the whole animal. Another 40% of the dose is excreted in urine as conjugates of the cis and trans isomers of 10-hydroxy-nortriptyline. Distribution studies demonstrate that the drug undergoes wide distribution, with the highest levels found in lung and liver. Nortriptyline was identified in the brain, showing that it does pass the blood-brain barrier; it also was found to be slowly, but efficiently, absorbed from the intestinal tract.

The metabolite pattern of d-propoxyphene in man. The use of heavy isotopes in drug disposition studies.

Abstract Through the combined use of deuterium labeling and GC-MS analysis, eight urinary metabolites of d-propoxyphene have been identified in man following a single oral dose of 130 mg of d-propoxyphene. The metabolites present were: norpropoxyphene, dinorpropoxyphene, cyclic dinorpropoxyphene, propoxyphene carbinol, norpropoxyphene carbinol, dinorpropoxyphene carbinol, p-hydroxypropoxyphene and p-hydroxynorpropoxyphene. The latter two metabolites occur as conjugates. The persistent metabolite, previously identified as norpropoxyphene, was found to be a mixture of norpropoxyphene and dinorpropoxyphene.

The mechanism of the oxidation of d-amphetamine by rabbit liver oxygenase. Oxygen-18 studies

Abstract The oxidation of d-amphetamine by rabbit liver microsomes has been studied using oxygen-18 as the source of oxygen. Incorporation of heavy oxygen into the two major metabolites phenylacetone oxime and phenylacetone, was 93–95% and 25–31% respectively. These data are consistant with a mechanism in which the initial step is the hydroxylation of the substrate at the carbon atom α to the amino group. The carbinol amine which is formed by this reaction then serves as the key intermediate from which ketone and oxime are formed. Thus, oxime can form from carbinol amine in two step, (1) dehydration of carbinol amine and (2) oxygenation of the resulting imine. Phenylacetone can form by two pathways (1) loss of a molecule of ammonia from carbinol amine (incorporation of oxygen from molecular oxygen) and (2) hydrolysis of oxime (incorporation of oxygen from water). In the case of d-amphetamine the hydrolytic route appears to be the more important as suggested by Hucker, et al. (4, 5).

Microsomal hydroxylation of ethylbenzene. Stereospecificity and the effect of phenobarbital induction

Abstract The microsomal monooxygenase system responsible for the oxidative metabolism of drugs has been studied intensively for the past decade. Considerable progress has now been made toward the understanding of the oxygen activating pathways of this syste, (cf. Omura et. al.). However the nature of the final step, the interaction of an activated oxygen species and substrate, is little understood. One probe of this reaction would be a study of the stereochemical nature of the reaction. The experiments presented here represent a reinvestigation of the hydroxylation of ethylbenzene to methylphenylcarbinol. In earlier work in intact rabbits, Smith, Smithies and Williams working with glucuronides found that both the D and L carbinols were formed although the ratio of D to L was not determined. We have now found that intact rats convert ethylbenzene to methylphenylcarbinol which is a mixture of 90.3% of the D(+) isomer and 9.7% of the L(-) isomer. In vitro hydroxylation in a microsomal preparation proved to be less stereospecific; the product contained 80.9% of the D(+) isomer. Studies with phenobarbital induced rats were of particular interest. In this case a reduction in stereospecificity was observed in both the in vivo and in vitro experiments. The role of the microsomal membranes in drug hydroxylations is discussed in light of these findings.

Reaction Pathways of in vivo Stereoselective Conversion of Ethylbenzene to (-)-Mandelic Acid

1. Mandelic acid formed in vivo from ethylbenzene as well as from various oxidation intermediates was laevo mandelic acid and was of surprisingly high optical purity. 2. Reaction sequences are proposed for the stepwise oxidation of ethylbenzene to mandelic acid. 3. Although the initial hydroxylation of ethylbenzene to methylphenyl-carbinol is stereoselective, the optical activity of mandelic acid is not established at this point since the optical centre is destroyed in the second step, dehydrogenation to acetopheneone. 4. Acetophenone appears to be a precursor of not only mandelic acid and benzoylformic acid but benzoic acid as well. 5. The route from acetophenone involves conversion to omega-hydroxyacetophenone and subsequent reduction to glycol and/or oxidation to phenylglyoxal. 6. The configuration of mandelic acid is determined either during reduction of hydroxyacetophenone or reduction of phenylglyoxal.

The metabolism of the herbicide diphenamid in rats.

Abstract The in vivo metabolism of the herbicide diphenamid (N.N-dimethyldiphenyl-acetamide) was studied in rats. The compound appeared to be well absorbed and relatively easily metabolized to excretable metabolites. The main route of metabolism was found to be N-dealkylation to nordiphenamid which in turn was excreted as an N-glucuronide. The most interesting metabolite found in urine was the O-glucuronide of N-methyl-N-hydroxymethyl diphenylacetamide. The N-hydroxymethyl compound, often suggested as an unstable intermediate in the N-demethylation reaction, was in this case stabilized by glucuronide formation and excreted in urine. A minor pathway of metabolism of diphenamid was found to be p-hydroxylation.

The difference in activity between (+)- and (-)-methadone is intrinsic and not due to a difference in metabolism.

The disposition and metabolism of (+)‐ and (‐)‐methadone has been compared in rats. At equal molecular doses, somewhat higher plasma levels of (‐)‐isomer were observed. At equal analgesic doses, brain and plasma concentrations of (+)‐methadone were at least 25 times greater than those of (‐)‐methadone. No qualitative differences were observed between isomers with respect to in vivo metabolic pattern or in vitro N‐demethylation rates. The results strongly support the conclusion that the large differences in analgesic potency between the isomers is due to an intrinsic difference in pharmacologic properties and is not related to a difference in disposition or metabolism.