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  • Title: Identification of major sulfate conjugates in the metabolism of propranolol in dog and man.
    Author: Walle T, Walle UK, Knapp DR, Conradi EC, Bargar EM.
    Journal: Drug Metab Dispos; 1983; 11(4):344-9. PubMed ID: 6137341.
    Abstract:
    A large portion of the dose of propranolol in animals and man is unaccounted for. Using radiotracer and HPLC techniques, five previously unrecognized polar and labile metabolites were found in dog urine, together accounting for 34% of the urinary radioactivity. The two main metabolites, peak 2 (7% of the radioactivity) and peak 4 (17%) could be isolated and purified by butanol extraction and reversed phase HPLC. Direct probe MS analysis of the main peak 4 and GC/MS analysis of the same peak after trifluoroacetylation both yielded 4-hydroxypropranolol. These observations together with UV spectra before and after acid hydrolysis indicated peak 4 to be an acid- and heat-labile conjugate of 4-hydroxypropranolol with the conjugating group at the phenolic oxygen atom. Arylsulfatase from Helix pomatia and Aerobacter aerogenes completely hydrolyzed peak 4 to 4-hydroxypropranolol. Urine and plasma as well as the antioxidant sodium bisulfite, however, markedly inhibited the arylsulfatase activity. After conversion of peak 4 to its sodium salt, a fast atom bombardment-positive ion mass spectrum confirmed this metabolite to be the sulfate ester of 4-hydroxypropranolol, clearly demonstrating the quasimolecular ion (M + H)+ at m/z 378 as well as fragmentation with loss of the sulfate moiety. The second largest unknown metabolite in the dog, peak 2, was identified as the sulfate ester of 4-hydroxypropranolol glycol. The 4-hydroxypropranolol sulfate was also identified in both urine and plasma of a patient treated with propranolol, accounting for approximately 18% of the dose.
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