Nonaromatic hydroxylation of bupivacaine during continuous epidural infusion in man.

Less than 11% of the dose of bupivacaine could be accounted for in urine from 10 patients receiving continuous epidural infusions. HPLC analysis of metabolites confirmed (S)-bupivacaine was more extensively metabolised than (R)-bupivacaine, and dealkylation was the predominant metabolic pathway although co-elution of metabolites made quantitation difficult. The percentage of (S)-2',6'-pipecoloxylidide and co-eluting metabolites excreted relative to (R)-2',6'-pipecoloxylidide from three patients was 0.32+/-0.05, while for seven patients it was 1.28+/-0.09. Conversely, the percentage of (S)-3'-hydroxy bupivacaine and co-eluants excreted relative to (R)-2',6'-pipecoloxylidide from the three patients (1.76+/-0.48) was greater than the seven patients (0.19+/-0.09). Urinary metabolites were analysed for evidence of aliphatic hydroxylation of bupivacaine. Chiral liquid chromatography-mass spectrometry (LC-MS) on an alpha(1)-glycoprotein column at pH 7 used hydroxylamine acetate as the volatile mobile phase. Compounds tentatively identified as hydroxybupivacaines by MRM were verified by their product ion spectra in a subsequent MS-MS run. Eighteen oxygenated metabolites of bupivacaine were detected, half of which were hydroxylated on nonaromatic groups. Equal numbers of mono- and dihydroxybupivacaines were excreted. There was no evidence to suggest the presence of (S)-4'-hydroxybupivacaine, 2'-hydroxymethylbupivacaine, 3'-hydroxy-2',6'-pipecoloxylidide or a piperidone. The metabolite previously identified as (S)-4'-hydroxybupivacaine was not hydroxylated on the xylyl group.