Glucuronidation of the Enantiomers of E-10-Hydroxynortriptyline in Human and Rat Liver Microsomes

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Abstract
Conjugation of racemic E-10-hydroxynortriptyline (E-10-OH-NT) with glucuronic acid was studied in the liver microsomal fraction of rats and humans. The diastereomeric glucuronides of E-10-OH-NT were resolved and quantitated by HPLC. Only the (+)-enantiomer was glucuronidated in liver microsomes from humans. Rat liver microsomes catalyzed the formation of both glucuronides. Phenobarbital pretreatment of rats increased the glucuronidation of both enantiomers about five-fold. The formation rate of (+)-E-10-OH-NT glucuronide varied from 5.5 to 33.2 pmol/mg .times. min, in microsomes from 13 humans. High activity was found in individuals previously treated with pentobarbital. Inhibition experiments with human liver microsomes showed that amitriptyline is a potent competitive inhibitor of (+)-E-10-OH-NT glucuronidation. p-Nitrophenol, paracetamol and 2-hydroxydesipramine also inhibited this reaction.