The in vitro reduction of dimethylpropion.

A study of the in vitro metabolism of dimethylpropion using different tissue homogenates of certain animals showed that: 1. Only the two major metabolites of dimethylpropion, i.e., methylpseudoephedrine and monomethylpropion were formed. 2. Species variation was observed with regard to the reductive ability of the liver homogenates. 3. Anaerobic conditions favored in vitro reduction to form methylpseudoephedrine. 4. The liver-soluble fraction exhibited the highest enzymatic reductive activity toward dimethylpropion. 5. Significant metabolic reduction of dimethylpropion was exhibited by the soluble fraction of the kidney.

Biological N-oxidation of piperidine in vitro.

The biological N-oxidation of piperidine, a pharmacologically active biogenic amine of mammals and human beings, was studied in vitro. After incubation of piperidine-HCl in a fortified rat liver microsomal preparation (9000 x g supernatant) at 37 degrees C for 30 min, 2 metabolites were detected. They were identified as N-hydroxy piperidine and 2, 3, 4, 5-tetrahydro-pyridine-1-oxide as evidenced by TLC, GLC, HPLC, GC-MS and MS.

The effect of food on the movement of pellets in the gastro-intestinal tract.

The effect of food on the movement of pellets in the gastro-intestinal tract was investigated in seven volunteers, either by means of X-rays taken after oral administration of barium sulfate pellets or by means of saliva concentration profiles of lithium obtained after oral administration of lithium sulfate controlled-release pellets. The X-ray studies showed that food had an effect on the time required for the pellets to leave the stomach and on their degree of dispersion in the small intestine, but not on other parameters. The studies with the lithium sulfate controlled-release pellets showed that food had a significant effect only in one in three subjects.

Metabolism of chlorpromazine and promazine in vitro: isolation and characterization of N-oxidation products.

1. The syntheses of the secondary hydroxylamines of nor1chlorpromazine and nor1promazine via their corresponding primary hydroxylamines and oximes are described. 2. The N-oxidation products are unstable to analysis by g.l.c. without prior derivatization; the decomposition products and the structures of the trimethylsilyl (TMS) and trifluoroacetyl (TFA) derivatives were characterized by g.l.c.-mass spectrometry. 3. Chlorpromazine, promazine and their demethylated products were shown to undergo metabolic N- and alpha-C-oxidation, to yield hydroxylamines and carboxylic acids, on incubation with fortified 9000 g liver homogenates of male New Zealand white rabbits. 4. A condensation product, an artifact formed by reaction of the metabolically derived primary hydroxylamines with acetaldehyde, an impurity in the extraction solvent, diethyl ether, was identified. 5. N-hydroxynor1- and N-hydroxynor2chlorpromazine undergo metabolic reduction to the parent amines, and the secondary hydroxylamine undergoes N-demethylation to yield the corresponding primary hydroxylamine.

Re-evaluation of the metabolism and excretion of diethylpropion in non-sustained and sustained release formulations.

A direct gas chromatographic method for unstable amino ketones, using a neutral column and moderately alkaline conditions during extraction has been developed. Its application has given a new perspective to the relative importance of the metabolic routes in the complex metabolism of diethylpropion which after oral administration in man is rapid and extensive (only 3-4% of the drug remains unchanged). Mono-N-de-ethylation is the main pathway (about 35% of the dose). N-De-ethylation is more important than carbonyl-reduction, occurring mainly with the unchanged drug (about 20% of the dose). Norephedrine, thought previously to be one of the main metabolites, has been shown to be present only in negligible amounts. About 30% of the dose, which cannot be accounted for as the sum of the amines recovered in urine, is probably metabolized by deamination, followed by oxidation and conjugation to give hippuric acid.

Bioavailability of amfepramone hydrochloride sustained release pellets formulation in healthy subjects.

The relative bioavailability and pharmacokinetic profile of two amfepramone (diethylpropion) hydrochloride oral preparations were evaluated in 12 normal volunteers using a newly developed gas-liquid chromatographic procedure to monitor the unchanged drug and its two major metabolites in urine, plasma and saliva. The sustained release pellets formulation (Regenon retard) provided excellent bioavailability and gave broad plateau levels extending over 6 to 8 h after administration, which were intermediate between the "peaks and troughs" shown by the same total dose of the free drug in three equal portions at 4-h intervals.

Bioavailability of controlled-release metoclopramide. 1st communication: single dose study.

The bioavailability of metoclopramide monochloride hydrate after single dose oral administration of a controlled-release capsule (Gastro-Timelets) was compared with that of oral metoclopramide monochloride hydrate solution in four normal volunteers. 30 mg of each product was administered to each subject in a cross-over manner on two separate occasions and plasma metoclopramide levels were measured using a HPLC method. Although peak plasma metoclopramide concentrations were lower, and occurred later after capsule treatment than after solution, analysis of the area under the plasma concentration-time curve (AUC) values for the two formulations demonstrated that the products were equivalent in terms of the extent of absorption, with the mean AUC value (0-30 h) for the capsule 943.7 ng/h/ml and that for the solution 896.2 ng/h/ml.

Bioavailability of controlled-release metoclopramide. 2nd communication: multiple dose study.

The bioavailability of metoclopramide monochloride hydrate after oral multidose administration of controlled-release metoclopramide capsules (Gastro-Timelets) was compared with that of oral metoclopramide monochloride hydrate solution in 10 healthy men. 30 mg of each product was administered to each subject in a cross-over fashion for 5 consecutive days and the plasma metoclopramide concentration was measured using a HPLC assay. Peak plasma metoclopramide levels were lower, and occurred later after controlled-release capsules administration than after solution. The graphs representing plasma metoclopramide levels after controlled-release formulation were smooth and devoid of sharp peaks and troughs. The area under the plasma metoclopramide level-time curve (AUC) values showed that the products were bioequivalent with the mean AUC values for the capsule (0-24 h) 837.9 ng/h/ml and (120-150 h) 993.2 ng/h/ml; and for the solution (0-24 h) 878.8 ng/h/ml and (120-150 h) 1054.0 ng/h/ml.

Simultaneous determination of amfepramon and its two major metabolites in biological fluids by gas liquid chromatography.

Sensitive and specific procedures based on gas liquid chromatography for the identification, separation and determination of amfepramon (diethylpropion) and its major metabolites ethylaminopropiophenone and diethylnorpseudoephedrine in human plasma, saliva and urine have been described. Acidification of the biological fluid samples has improved the stability of the compounds under conditions of storage.

Evaluation of the percutaneous absorption and metabolism of some aminopropiophenones.

The absorption of diethylpropion (DEP I), dimethylpropion (DMP I) and some of their basic metabolites into and passage through the skin was investigated and a comparison of their metabolism following oral and percutaneous administration made. High percentages (60-80%) of DEP I and its metabolites and a small percentage of DMP I and its metabolites were taken up into the skin in less than 2 min--the remaining percentages of the compounds were absorbed into the skin by a first order process. The rate of appearance of the compounds in the blood, which reflects their rate of passage through the skin, did not correlated with their rate of absorption into the skin. More metabolism occurred with all the compounds after their oral administration than after their percutaneous application.

Liminal therapy: a strategy for the complete and selective destruction of malignant tissue in situ.

The property of aerobic glycolysis commonly possessed by malignant cells points to a weakness in oxidative metabolism which has been equated in some tumours with partial uncoupling of oxidative phosphorylation. The suggestions are made, first, that this endogenous defect may account for spontaneous cell death in situ, and, second, that its accentuation would inflict extensive tumour injury upon sensitive neoplasms. Certain drugs not in current use for the treatment of malignant disease are known to be able to interfere selectively with energy metabolism in sensitive tumours to such an extent that widespread necrotization ensues. The drugs activate an endogenous destructive mechanism that appears to require oxygen. Liminal therapy, the maintenance of continuous destructive pressure on sensitive growths in such a manner that maximal anti-tumour activity in terms of interference with energy production is not achieved at any one time, and under conditions in which the oxygen supply is only partly depleted, is put forward as a possible means of achieving complete and selective tumour destruction in vivo.

Metabolism of imipramine in vitro: synthesis and characterization of N-hydroxydesmethylimipramine.

The synthesis of N-hydroxydesmethylimipramine via the corresponding primary hydroxylamine and oxime is described. The N-oxygenated products are unstable to g.l.c. analysis without prior derivatization; the decomposition products are identified by g.l.c.-mass spectrometry. N-Hydroxydesmethylimipramine is shown to be a metabolite of imipramine and desmethylimipramine on incubation of either with fortified 9000 g liver homogenates of male New Zealand white rabbits. The metabolic product is characterized by mass spectrometry and n.m.r. Didesmethylimipramine is shown to undergo metabolic alpha-C-oxidation, to yield the carboxylic acid, 3-(10,11-dihydro-5H-dibenz[b, f]azepin-5-yl)propionic acid, but not N-oxidation. N-Hydroxydesmethylimipramine is metabolically reduced to desmethylimipramine and metabolized further to 10-hydroxydesmethylimipramine, 2-hydroxydesmethylimipramine and the carboxylic acid. The possible role of N-hydroxydesmethylimipramine and 3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)propionic acid in the formation of iminodibenzyl is discussed.

Metabolic oxidation of desmethylchlorimipramine in vitro by 9000 g rabbit-liver preparations.

1. The metabolism of desmethylchlorimipramine (I) has been investigated in vitro using fortified 9000 g liver homogenates of male rabbits. 2. Four metabolic products: N-hydroxydesmethylchlorimipramine (II), 3-(3-chloro-10, 11-dihydro-5H-dibenz[b,f]azepin-5-yl)propanoic acid (III), 10/11-hydroxydesmethylchlorimipramine (IV) and 2/8-hydroxydesmethylchlorimipramine (V) were isolated and identified by electron-impact mass spectrometry and n.m.r. spectroscopy. 3. Desmethylchlorimipramine (I) undergoes both N- and alpha-carbon oxidation in addition to aromatic and alicyclic carbon oxidation.