Search PubMed⌕ Search

Biomedical subjects

M Jarman

Publications and source records attributed to M Jarman.

At least 127 records · Page 7Linked to original sources
PubMed1978

Metabolism of N-nitrosomorpholine by the rat in vivo and by rat liver microsomes and its oxidation by the Fenton system.

N-Nitrosomorpholine is converted into N-nitroso-2-hydroxymorpholine by rat liver microsomes and by the Fenton oxidation system. The hydroxy derivative was also synthesised by the oxidation of N-nitrosodiethanolamine with permanganate and characterized as the methoxime and the 2,4-dinitrophenylhydrazone. The Fenton system also afforded products believed to be N-nitroso-2-morpholone, and the 2-hydroperoxy- and 2-peroxy-derivatives of N-nitrosomorpholine. The only urinary metabolite definitely identified was N-nitrosodiethanolamine. The significance of metabolic 2-hydroxylation in relation to the carcinogenic action of N-nitrosomorpholine is discussed.

Animals↗
PubMed1977

The metabolism and antitumour activity of the enantiomers of cis- and trans-4-methylcyclophosphamide.

4-Methylcyclophosphamide, an analogue of the antitumour agent cyclophosphamide, exists in cis and trans forms, each of which comprises a pair of optical isomers. The extents of metabolism by rat liver microsomes during 20 min were compared for the four steroisomers incubated separately, and for the racemic cis and trans-derivatives in admixture, using mass spectrometry and gas chromatography respectively. In comparative antitumour tests against the ADJ/PC6 plasma cell tumour in mice, the racemic cis and trans forms of 4- and 6-methylcyclophosphamide had similar therapeutic indices. The four stereoisomers of 4-methylcyclophosphamide exhibited an approx. two-fold range in therapeutic index so that there was no marked effect on either metabolism or antitumour activity occasioned by change of configuration either at C-4 or at phosphorus.

Animals↗
PubMed1976

The use of deuterated analogs in qualitative and quantitative investigations of the metabolism of cyclophosphamide (NSC-26271).

Ring-deuterated analogs of cyclophosphamide (CP) (4-d2, 5-d, 4,6-d4, and 4,5,6-d6 derivatives) have been used to study the influence of deuterium substitution on the rates of metabolic pathways involving oxidation at C-4, and on the rate of elimination of acrolein from aldophosphamide. The magnitude of the deuterium isotope effect (kH/kD) associated with appropriate C-deuteration has been related to antitumor activity against the ADJ/PC6 murine plasma cell tumor. Isotope effects of 2.2 and 1.8 respectively, for the formation of 4-ketocyclophosphamide (4-keto-CP) and carboxyphosphamide, caused little or no change in antitumor activity (4-d2 and 4,6-d4 analogs compared with CP), but an isotope effect of about 5.3 for the beta-elimination pathway, consequent on 5,5-dideuteration, was paralleled by a marked drop in potency (7-13-fold increase in ED90) of 5,5-dideuterated analogs compared with that of CP. Analogs tetradeuterated in the bis(2-chloroethyl)amino function were used to quantitate CP and 4-keto-CP in human plasma and urine using stable-isotope dilution and direct-insertion electron impact mass spectrometry. The negative optical rotation of CP recovered from human urine after administration of the racemlc drug gave evidence for stereoselectivity in the metabolism.

Acrolein↗
PubMed1975

The quantitation of cyclophosphamide in human blood and urine by mass spectrometry-stable isotope dilution.

The levels of cyclophosphamide in the blood and the urine of patients have been monitored by direct insertion, electron impact mass spectrometry using the principle of stable isotope dilution. When a tetradeuterated analogue of the drug was added to a sample of blood or urine the concentration of cyclophosphamide could be determined from the ratio of the intensities of the signals (M-CH2 C1) characteristic for cyclophosphamide and the tetradeuterated analogue present in the mass spectrum of a chloroform extract. The procedure is highly specific for cyclophosphamide and obviates the need to use radioactively labelled cyclophosphamide for quantitation of the drug in man.

Carcinoma, Small Cell↗
PubMed1975

Synthesis of deuterium-labeled analogs of cyclophosphamide and its metabolites.

Convenient syntheses are described of d4 analogs of cyclophosphamide and some of its metabolites, potential standards for the quantitative analysis of the drug and its metabolites in human body fluids by stable isotope dilution-mass spectrometry. Base-catalyzed H-D exchange on N-nitrosobis(2-hydroxyethyl)amine gave N-nitrosobis(1,1-dideuterio-2-hydroxyethyl)amine from which bis(2-chloro-1,1-dideuterioethyl)amine (nor-HN2-d4) was readily obtained. Established synthetic routes were then used to convert nor-HN2-d4 into d4 analogs of cyclophosphamide [2-[bis(2-chlorethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide], 4-ketocyclophosphamide [2[BIS(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorin-4-one 2-oxide], and carboxyphosphamide [2-carboxyethyl N-N-bis(2-chloroethyl)phosphorodiamidate], and these analogs were used in a preliminary investigation into the quantitation of the appropriate components in human plasma and urine. Also prepared were d4 analogs of phosphoramide mustard [N,N-bis(2-chloroethyl)phosphorodiamidic acid (cyclohexylammonium salt)] and 3-(2-chloroethyl)oxazolidone and the methyl and trideuteriomethyl esters of phosphoramide mustard.

Chromatography, Ion Exchange↗
PubMed1975

Isolation and identification of products from alkylation of nucleic acids: ethyl- and isopropyl-purines.

Ethylation and isopropylation of guanine in alkaline solution, or of adenine in formic acid, by alkyl methanesulphonates gave the following products: 1-, N2-, 3-, O6-, 7- and 9-alkylguanines; 1-, 3-, 7- and 9-alkyladenines. The products were identified from their characteristic u.v-absorption spectra, by comparison with either known ethyladenines or with the corresponding known methyladenines, and were also characterized by mass spectrometry. Their chromatographic properties on paper, t.l.c. and various columns were determined. DNA was alkylated in neutral solution with 14C-labelled alkyl methanesulphonates and the ratios of the alkylpurines formed were obtained, and compared for alkylation by methyl, ethyl and isopropyl methanesulphonates and by N-methyl-N-nitrosourea. The extents of alkylation at O-6 of guanine relative to those at N-7 of guanine varied with the reactivity of the methylating agents according to the predictions of Swain & Scott (1953) relating nucleophilicity of the groups alkylated with the substrate constants of the alkylating agents. The relative extents of alkylation at N-3 of adenine did not follow this correlation.

1-Propanol↗