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.

Quantitation of propoxyphene and its major metabolites in heroin addict plasma after large dose administration of propoxyphene napsylate.

A sensitive and specific GLC assay method was developed for the determination of propoxyphene, its major metabolite norpropoxyphene, and lesser known metabolites cyclic dinorpropoxyphene and/or dinorpropoxyphene in plasma of heroin addicts administered up to 800 mg of propoxyphene napsylate. The assay used a mass internal standard of pyrroliphene. The compounds were extracted from pH 9.8 carbonate-buffered plasma with butyl chloride, back-extracted into acidified water which was then washed with hexane, and reextracted with chloroform from the aqueous phase made basic. Quantitation of the drug and its metabolites was accomplished by temperature-programmed GLC. Absolute identification of the compounds chromatographed was completed by GLC-mass spectrometry.

Pharmacokinetics of the anticancer agent sulofenur in mice, rats, monkeys, and dogs.

The absorption and pharmacokinetics of sulofenur [N-(indan-5-sulfonyl)-N'-(4-chlorophenyl)urea, LY186641] and its major metabolites were examined in mice, rats, monkeys, and dogs. The compound is a diarylsulfonylurea currently being evaluated as an oncolytic agent in phase I and II trials. In all species, sulofenur was well absorbed after an oral dose, but over a prolonged period, and sulofenur exhibited a fairly long half-life of elimination from plasma. These values ranged from 6 h in rats up to 30, 110, and 200 h in mice, monkeys, and dogs, respectively, at doses (240-1000 mg/m2) within the range of those used in clinical trials. Experiments describing the high degree of binding of sulofenur to plasma proteins (consistently > 99%) help to explain these relatively long half-lives. There is, however, a large difference between these plasma half-lives in the species studied. Sulofenur was previously found to be extensively metabolized to products that are excreted primarily into the urine. In this study, its major metabolites, which are found mainly in the urine, were also minor components of the drug-related material (< 10% of the sulofenur concentrations) in the plasma of rats treated with sulofenur. The absorption, binding characteristics, and elimination of these major metabolites after their administration to rats were also compared with sulofenur.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Simultaneous measurement of plasma levels of d-Propoxyphene and l-Propoxyphene using stable isotope labels and mass fragmentography.

When racemic propoxyphene was administered orally to dogs, plasma levels of d-propoxyphene were higher than those of l-propoxyphene. The half-life of d-propoxyphene was also longer than that of the l-isomer. Measurements were performed by labeling one isomer of a racemic mixture with deuterium and then measuring d- vs. l- ratios by mass fragmentography. An intravenous experiment was also performed and confirmed the preferential uptake of the levo isomer. To do these experiments successfully propoxyphene isomers were labeled on the benzyl methylene with deuterium atoms. In vivo studies demonstrated that this labeling position was sufficiently far removed from the point of metabolic attack in the molecule so that no interfering isotope effect existed. The methodology outlined in this paper will be of great value in the study of the disposition of the individual isomers of racemic drugs.

Reduction of levopropoxyphene N-oxide to propoxyphene by dogs in vivo and rat liver microsomal fraction in vitro.

1. When l-propoxyphene-N-oxide was given orally to dogs, reduction occurred in vivo resulting in substantial plasma levels of l-propoxyphene. 2. When l-propoxyphene-N-oxide was given intravenously, near peak plasma levels of propoxyphene occurred in 10 minutes. This suggests that reduction is occurring at least in part in mammalian tissue rather than in gut flora. 3. Levopropoxyphene oxide was also readily reduced anaerobically in a rat liver microsomal fraction. 4. Results from this study explain our early observation that while l-propoxyphene-N-oxide is demethylated in vivo, demethylation does not occur in vitro when the oxide is incubated in air with liver homogenate. Thus demethylation of the oxide can occur only after reduction of the oxide to the tertiary amine. While reduction occurs readily in vivo it is completely inhibited by oxygen present in the usual microsomal incubation. 5. These studies further confirm that the N-oxide is not an intermediate in the demethylation of propoxyphene.

Metabolism of oral cephalothin and related cephalosporins in the rat.

The fate of orally administered [(14)C]cephalothin has been studied in the rat. This antibiotic undergoes degradation in the gut followed by the subsequent absorption of a portion of the degradation products. About 50% of the administered radioactivity appears in the urine as a mixture of thienylacetylglycine, thienylacetamidoethanol and an unidentified polar metabolite. Evidence is presented indicating that thienylacetamidoethanol arises by the enzymic reduction of a metabolic intermediate, thienylacetamidoacetaldehyde. The metabolic fate of cephalothin is very similar to that of cephaloram reported earlier. The fate of [(14)C]cephaloridine and 7-phenoxy[1-(14)C]acetamidocephalosporin was also investigated. In addition to the expected metabolites, about 5% of the cephaloridine dose is absorbed unchanged. With 7-phenoxy[1-(14)C]acetamidocephalosporin, 15% of the dose is recovered in urine as deacetyl-7-phenoxy[1-(14)C]acetamidocephalosporin.

Simultaneous estimation of propoxyphene-do and propoxyphene-d2 levels by quantitative mass fragmentography. Potential utility in multidose investigations.

A quantitative mass fragmentographic method for the simultaneous determination of labeled and unlabeled propoxyphene in plasma is described. Dogs treated daily with propoxyphene-do were treated with a pulse dose of propoxyphene-d2 at day 20. It was found that following an initial rapid equilibrium phase levels of propoxyphene-d2 fell more rapidly than those of propoxyphene-do. This result suggests that 'deep' pools of tissue bound propoxyphene exist which exchange very slowly with drug present in the central compartment. Experimental evidence is presented which demonstrates that the difference in behavior of propoxyphene-do and -d2 is not due to unanticipated secondary isotope effects.

Propoxyphene: pathways of metabolism in man and laboratory animals.

Through the combined use of stable isotope labeling and gas chromatographic mass spectrometric analysis, the metabolic patterns for propoxyphene have been determined in laboratory animals and man. The rat and dog eliminated propoxyphene and its metabolites principally via the bile, while the rabbit more closely resembled man in excreting the metabolic products into urine. Metabolites in rat and rabbit existed as conjugates, whereas in dog and man the metabolites were excreted as a mixture of the free and unconjugated forms. The primary route of metabolism in all species studied was N-demethylation. However, the rat and rabbit extensively hydroxylated propoxyphene and its metabolites prior to elimination. Metabolites arising from ester hydrolysis were found in rat and man. N-acetylated products were identified in all four species. A metabolite formed from cyclization and dehydration of dinorpropoxyphene was isolated in urine and was further identified as a circulating metabolite in dog plasma.

Biosynthesis of thromboxane B2: assay, isolation, and properties of the enzyme system in human platelets.

The microsomal fraction of human platelets catalyzed the conversion of arachidonic acid to an unstable platelet-aggregating factor and a hydrolyzed product on the thin-layer chromatography (TLC). This product was isolated on TLC, purified by silica gel column chromatography and identified by combined gas chromatography-mass spectrometry as the hemiacetal derivative of 8-(1-hydroxy-3-oxopropyl)-9, 12L-dihydroxy-5, 10-heptadecatrienoic acid (thromboxane B2). The enzymatic activity was dependent upon methemoglobin and tryptophan as cofactors. Reduced glutathione had no effect either alone or in combination with other cofactors. Methemoglobin could be replaced by hematin or hemin; and tryptophan by 3-indolacetic acid or catecholamines. The apparent requirement for methemoglobin is due to the reductive activity of ferriprotoporphyrin IX. The reaction, however, catalyzed by the ferriprotoporphyrin IX in the thromboxane synthesizing system is different from that described for the decomposition of lipid peroxides. Certain transition metals and hydrogen donors, such as hydroquinone and ascorbate, which have been shown to stimulate the catalytic activity of ferriproroporphyrin IX in the decomposition of 15-hydroperoxy-prostaglandin E1 are inhibitors of thromboxane B2 formation. This enzyme preparation also transformed eicosa-8. 11, 14-trienoic acid to an unknown product on TLC. The enzyme system was rapidly inactivated upon incubation in the reaction mixture.

Species differences in the metabolism of alpha-1-trans-4-dimethylaminotetrahydro-3-furyl-cyclohexanephenylglycolate, an experimental anticholinergic agent.

Metabolism studies in the rat, dog and cat have demonstrated a definite species difference in biotransformation and elimination of alpha-1-trans-4-dimethylaminotetrahydro-3-furylcyclohexanephenylglycolate (Lilly 82537), an experimental anticholinergic agent. Separation and identification of urinary and biliary metabolites by gas chromatographic mass spectrometric analysis has shown three mechanisms to be involved in the metabolism of Lilly 82537 in these species; N-demethylation, aliphatic hydroxylation ahd ester hydrolysis. A major portion of the drug administered was eliminated unaltered in the cat and dog, while only trace quantities of parent drug were observed in the urine and bile of rats. These metabolic differences may be responsible for observed species differences in the pharmacologic activity of Lilly 82537.