[Stable isotopes in the biopharmaceutical research. II].
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Biomedical subjects
Publications and source records attributed to A Frigerio.
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The disposition of cyclophosphamide (CP) in mice bearing Lewis lung tumor has been studied by chemical ionization-mass fragmentography using isophosphamide as the internal standard. The drugs were analyzed as their N-trifluoroacetyl derivatives in order to increase sensitivity and to avoid column adsorption and decomposition phenomena. The minimum detectable amount was 500 pg/injection. Linearity was found up to microgram amounts of the substance without any interference of endogenous compounds.
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The epoxide metabolites of two clinically used drugs and an experimental psychotropic agent, carbamazepine 10,11-oxide, cyproheptadine 10,11-oxide and cyclobenzaprine 10,11-oxide, were fully devoid of any mutagenic activity under conditions where K-region-epoxide metabolites of some known carcinogens, such as benzo(a)pyrene, proved to be potent frameshift mutational agents for Salmonella typhimurium TA 1537 and TA 1538. All epoxides tested were non-mutagenic for TA 1535, designed to detect substitution mutations. The 10,11-epoxides of the three drugs, carbamazepine, cyproheptadine and cyclobenzaprine, were not cytotoxic to any of the bacterial tester strains used, precluding that mutagenicity might have been overshadowed by cytotoxicity. When the mutagen, precursor, benzo(a)pyrene, was incubated together with TA 1537 and a mammalian microsomal preparation in the presence of a system generating the co-factor necessary for mono-oxygenase activity, activation to mutagenic species was observed which was dramatically increased in the presence of a potent epoxide hydratase inhibitor, 1,1,1-trichloropropene 2,3-oxide, suggesting epoxide(s) as the (or one of the) mutagenically active species metabolically produced in situ. None of these effects was observed with the three medical drugs. Moreover, the observation that the alkene oxide 4-phenylstyrene 7,8-oxide is mutagenic to the two strains TA 1537 and TA 1538 but the K-region arene oxide derived from 7,12-dimethylbenz(a)anthracene is inactive for the latter strain indicates that epoxidation of an aromatic double bond of a polycyclic hydrocarbon is neither a necessary nor a satisfying condition for frameshift mutagenesis to occur.
A sensitive and specific combined gas chromatographic-mass fragmentographic method for the determination of trazodone in rat plasma is described. After extraction with diethyl ether and washing of the extracts in order to prevent interference from endogenous materials, trazodone and the internal standard benperidol were separated on an OV-1 column. The minimum amount of trazodone detected was 20 ng by gas chromatography with the use of a flame ionization detector and 200 pg when using the mass fragmentographic technique. Plasma levels in rats treated with a single intravenous dose (10 mg/kg) of trazodone are also reported.
A sensitive and specific method for the simultaneous determination of imipramine and desipramine in the blood plasma of depressed patients under treatment that involves separation by gas chromatography and detection by mass fragmentography is described. Concentrations were determined by focusing the mass spectrometer upon the ions at m/e 280 and 235 for imipramine and 308, 236 and 114 for desipramine (N-acetyl derivative), while promazine was used as the internal standard (ions at m/e 284 and 238). Determinations are possible at levels as low as 10 ng/ml in plasma.
A method is described for the determination C3-hydroxylated benzodiazepine glucuronides in biological samples. Oxazepam and lorazepam glucuronides are measured as methyl esters and trimethylsilyl derivates by a gas chromatographic procedure. The applicability of the method has been tested on the urine of rats, guinea pigs, rabbits and man, receiving oxazepam orally. Oxazepam glucuronide was not found in rat urine but it was present in the urine of rabbits (5.7% of the administered dose), guinea pigs (9.5%) and man (13.4-26.9%).
1. A gas chromatographic-mass fragmentographic method has been developed to determine piribedil and its metabolite S-584, using diazepam as internal standard. The metabolite was derivatized as a trimethylsilyl ether for gas chromatographic analysis. The minimum detectable amount of piribedil and the metabolite was 10 ng/g tissue. 2. Levels of piribedil and its metabolite in the striatum were determined by mass fragmentography.
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The metabolism of carbamazepine-10,11-epoxide, after administration of the epoxide to rats has been studied. The iminostilbene epoxide and the 10,11-dihydrodiol of the iminostilbene have been identified as metabolites of carbamazepine-10,11-epoxide by means of gas chromatographic and gas chromatographic-mass spectrometric techniques.
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10,11-Dihydro-10,11-dihydroxyprotriptyline was identified in rat urine following administration of protriptyline 40 mg kg-1 i.p. Gas chromatographic-mass spectrometric characterization confirmed the structure of this stable metabolite, and its identity with a synthetic sample.
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