High-pressure liquid chromatography coupled with a radioactivity detector: investigation into the biotransformations of tritium and carbon-14 labeled compounds.
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Biomedical subjects
H A Dugger
Publications and source records attributed to H A Dugger.
Biotransformation of mazindol. II. Absorption and excretion in the dog and man.
On administration of tritium-labeled mazindol (l) to man and the dog, absorption was slow but complete. Excretion was slow in both dog and man, but the dog did excrete the drug and/or metabolites faster than man. Blood levels of l in man after a single oral dose of a 2-mg tablet reached a peak value of 2.5 ng/ml, which remained essentially unchanged for at least 6 hr. After multiple doses of a 2-mg tablet t.i.d. for 4 days to subjects who had been receiving nonlabeled l, 2 mg t.i.d. for 6 months, the blood level reached a maximum concentration of 10.8 ng/ml, measured 2 hr after the last dose on day 4. This value is somewhat higher than predicted by the single-dose data, indicating that in man, mazindol does not induce its own metabolism.
Absorption↗
Biotransformation of mazindol. III. Comparison of metabolism in rat, dog, and man.
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Biotransformation of mazindol. I. Isolation and identification of some metabolites from rat urine.
Three metabolites of tritium-labeled mazindol were isolated from rat urine by the inverse isotope-dilution technique in which the labeled metabolites were synthesized by a second, smaller group of rats. These metabolites were isolated by Amberlite XAD-2 chromatography and silica gel column and preparative thin-layer chromatography. The major metabolite (II) was shown by mass spectrometry of its trimethylsilyl derivative. NMR spectroscopy, and degradation studies to be 5-(p-chlorophenyl)-2,5-dihydro-5-hydroxy-3H-imidazol(2,1-a)isoindol-3-one. A comparison of its mass spectrum with that of an authentic sample prepared from 1-(p-chlorophenyl)-3-ethoxy-1-methoxy-1H-isoindole and glycine ethyl ester confirmed the assignment. Metabolite III was shown by its mass spectrum, NMR spectrum, degradation, and analogy with metabolite II to be 5-(p-chlorophenyl)-2,5-dihydro-2,5-dihydroxy-3H-imidazo (2,1-a)isoindol-3-one. Only a small amount of metabolite IV was isolated as an artifact, 3-(p-chlorophenyl)-2-glycyl-3-methoxy-1-isoindolinone, as shown by its mass spectrum and degradation to 2-(p-chlorobenzoy)benzoic acid. The metabolite IV is believed to be the corresponding 3-hydroxy compound. Synthesis of IV by base-catalyzed hydrolysis of metabolite II supports the structural assignment. In addition, the facile conversion of synthetic IV into the corresponding 3-methoxy derivative by acidic methanol was also observed.
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