NEW RING-HYDROXYLATED METABOLITES OF PROPRANOLOL - SPECIES-DIFFERENCES AND STEREOSPECIFIC 7-HYDROXYLATION

  • 1 January 1982
    • journal article
    • research article
    • Vol. 10  (2) , 122-127
Abstract
The structures of several unknown, potentially active, monohydroxylated metabolites of (.+-.)-propranolol in rats, dogs and man were studied. The metabolites were isolated from urine by extraction with ethyl acetate at pH 9.6 after enzymatic hydrolysis. They were then separated as their trimethylsilyl and trifluoroacetyl derivatives and detected by flame-ionization GLC or gas chromatography/mass spectrometry. Structure identification of the metabolites was based on a comparison of their GLC retention times and mass spectra with those of the 7 synthetic isomeric hydroxypropranolols (HO-P). Three metabolites not previously described, 2-HO-P, 5-HO-P and 7-HO-P, and the known 4-HO-P were identified in the rat. 2-HO-P accounted for .apprx. 1% of total monohydroxylated propranolol, 5-HO-P for 7 .+-. 2%, 7-HO-P for 26 .+-. 5% and 4-HO-P for 66 .+-. 5%. The separate administration of (+)- and (-)-propranolol demonstrated stereospecific 7-hydroxylation of (+)- and (-)-propranolol in the rat. The formation of 5-HO-P was selective for the (-)-isomer, whereas 4-hydroxylation was not stereoselective. The recovery of the dose as the monohydroxylated metabolites in urine was considerably higher after (+)-propranolol, 49 .+-. 9%, than after (-)-propranolol, 32 .+-. 6%. 4-HO-P was the only hydroxylation product in the dog, whereas in man small quantities of 2-HO-P, 5-HO-P and 7-HO-P were observed in addition to 4-HO-P.