title: Nonaromatic hydroxylation of bupivacaine during continuous epidural infusion in man.
abstract: 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.
authors.affiliation: School of Pharmacy, University of Otago, P.O. Box 913, Dunedin, New Zealand. robin.ledger@stonebow.otago.ac.nz
authors.forename: Robin
authors.initials: R
authors.lastname: Ledger
mesh_terms: D015360:Analgesia, Epidural; D000779:Anesthetics, Local / Q000008:administration & dosage / Q000652:urine*; D002045:Bupivacaine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000737:chemistry / Q000652:urine*; D002853:Chromatography, Liquid / Q000379:methods*; D006801:Humans; D006841:Hydrocarbons, Aromatic / Q000652:urine; D006900:Hydroxylation; D007263:Infusions, Parenteral; D007268:Injections, Epidural; D008297:Male; D013058:Mass Spectrometry / Q000379:methods*; D008657:Metabolic Clearance Rate; D013237:Stereoisomerism; D016482:Urinalysis / Q000379:methods*
chemical_list: D000779:Anesthetics, Local; D006841:Hydrocarbons, Aromatic; C051879:4'-hydroxybupivacaine; C025149:2',6'-pipecoloxylidide; D002045:Bupivacaine