IDENTIFICATION OF GLUCURONIDE METABOLITES OF BENZOMORPHAN NARCOTIC ANALGESIC DRUGS IN BILE FROM ISOLATED PERFUSED RAT-LIVER BY GAS-CHROMATOGRAPHY AND MASS-SPECTROMETRY

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  • 1 January 1977
    • journal article
    • research article
    • Vol. 5  (1) , 47-55
Abstract
The metabolism of 4 benzomorphan compounds was studied in the isolated perfused rat liver, and glucuronide metabolites were identified by combined gas chromatography-mass spectrometry (GC/MS). Cyclazocine, ketocyclazocine, volazocine and pentazocine were each added to the perfusate of the isolated perfused rat liver and the bile collected for 3 h. The residue from evaporation of the bile was derivatized with the dimethylsulfoxide anion and methyl iodide, and the permethylated glucuronide metabolites were identified by GC/MS. The 4 compounds were hydroxylated by the liver and excreted in the bile as phenolic glucuronides. For example, permethylated hydroxycyclazocine glucuronide had a mass spectrum with a molecular ion at m/e [mass-charge ratio] 533 and fragment ions at m/e 301 (aglycone), m/e 260 (loss of cyclopropyl group) and prominent ions at m/e 232, 201, 169, 141 and 101 caused by fragmentation of the permethylated glucoronic acid moiety. Perdeuteriomethylation demonstrated that pentazocine, volazocine and cyclazocine were further metabolized by methylation of 1 hydroxy substituent and glucuronidation on the other. Pentazocine, cyclazocine and ketocyclazocine were also metabolized to phenolic glucuronides of the parent drugs. N-dealkylated metabolites of pentazocine, volazocine and cyclazocine were identified both as permethylated glucuronic acid conjugates and as the trimethylsilyl derivatives of the aglycones, obtained by enzymatic hydrolysis of the conjugates in bile.