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.

Degradation of (--)-ephedrine in solution and during extraction with diethyl ether.

Significant losses occurred during the extraction of small quantities of ephedrine from aqueous media using either regular or analytical grades of diethyl ether. The losses were, at least in part, caused by reaction of the ephedrine with aldehydic impurities in the ether; three substituted oxazolidines were identified, using g.l.c. and g.l.c-ms. These and one other oxazolidine were synthesized and characterized by g.l.c., g.l.c.-ms, nmr and infrared spectroscopy. Alternative mechanisms for ephedrine breakdown were considered. Ephedrine was separately oxidized by three different oxidizing agents and also irradiated by ultraviolet light; the products were characterized by g.l.c., g.l.c.-ms. A method for the purification of diethyl ether is recommended to minimize ephedrine breakdown.

A reappraisal of the stereoselective metabolism of nicotine to nicotine-1'-N-oxide.

1. The cis and trans 1'-N-oxide metabolites of (2'R)-(+)-nicotine have the absolute configuration (1'S; 2'R) and (1'R; 2'R), respectively, and not the reverse as previously published. 2. Reinterpretation of metabolic data in the light of this reassignment reveals that N-oxidation of nicotine leads preferentially to the (1'R)-N-oxide, with little dependence on the configuration of the 2'-centre. 3. It is proposed that (2'S)-(-)-nicotine and (2'R)-(+)-nicotine bind to the same enzymic site by two distinct modes of binding; each of these modes involves the more basic centre (in this case the pyrrolidine ring) as the governing binding moiety.

The influence of smoking on the intersubject variation in pentazocine elimination.

The cumulative urinary excretion over 24 h of pentazocine, under conditions of acidic urinary pH, has been measured in smokers and non-smokers using both male and female subjects (seventy subjects in total). A restricted urban population was studied. An overall three-fold inter-subject variation in elimination was observed. The cumulative urinary excretion of pentazocine was normally distributed in both smokers and non-smokers. Smokers metabolize 40% more pentazocine than non-smokers. It is concluded that induction is principally responsible for the observed subject variability.

The metabolism of N-ethyl-N-methylaniline by rabbit liver microsomes: the measurement of metabolites by gas-liquid chromatography.

1. A method for the determination of N-ethyl-N-methylaniline and its metabolites by g.l.c. is described. 2. Following incubation in N-ethyl-N-methylaniline with rabbit liver microsomes for 60 min, over 95% of the substrate was accounted for as unchanged compound or metabolites. 3. N-Ethyl-N-methylaniline is metabolized in vitro by rabbit tissues mainly by N-oxidation and N-demethylation and to a lesser extent by N-deethylation and di-dealkylation. 4. Both major routes of metabolism were observed in homogenates prepared from rabbit liver and lung; in addition N-oxidation occurred in kidney and bladder tissue homogenates.

The differentiation of N-oxidation and N-dealkylation of N-ethyl-N-methylaniline by rabbit liver microsomes as distinct metabolic routes.

1. N-Oxidation and N-dealkylation were shown to be separate routes of metabolism for N-ethyl-N-methylaniline. 2. N-Dealkylation, but not N-oxidation, is enhanced when NADH is present in addition to the NADPH-regenerating cofactors. 3. Some inhibitors, e.g. p-chloromercuribenzoate, inhibit N-dealkylation to a very much greater extent than they do N-oxidation. 4. N-Dealkylation is affected more by 'ageing' of the microsomal preparation or by the presence of bile salts, than is N-oxidation. 5. N-Oxidation followed by N-O-alpha-carbon migration of oxygen is only implicated to a very minor extent in the N-dealkylation process.

Metabolism of phenothiazines: identification of N-oxygenated products by gas chromatography and mass spectrometry.

The solid inlet mass spectra of the N-oxide and N-oxide sulphoxide metabolites of promazine, chlorpromazine and methotrimeprazine have been determined at different temperatures and compared with the mass spectra of the main thermolytic product of the N-oxides and N-oxide sulphoxides obtained during combined gas chromatography-mass spectrometry. Diagnostic ions were produced by direct insertion of the compounds at ambient temperature into the mass spectrometer. These ions distinguish the N-oxides of arylalkyl tertiary amines from the N-oxygenated derivatives of primary and secondary arylalkylamines.