Enantioselective hydroxylation of nortriptyline in human liver microsomes, intestinal homogenate, and patients treated with nortriptyline

Ther Drug Monit. 1991 May;13(3):189-94. doi: 10.1097/00007691-199105000-00001.


The enantioselectivity of hydroxylation of nortriptyline (NT) to E-10-hydroxynortriptyline (E-10-OH-NT) was studied in human liver microsomes, intestinal homogenate, and patients treated with NT. The rate of formation of (-)-E-10-OH-NT was higher than that of (+)-E-10-OH-NT both in the liver microsomes and in the intestinal homogenate. Quinidine, a prototype competitive inhibitor of the cytochrome P450IID6 ("debrisoquin hydroxylase"), inhibited the formation of (-)-E-10-OH-NT in a concentration-dependent manner in liver microsomes, while the formation of (+)-E-10-OH-NT was hardly affected. This indicates that P450IID6 catalyzes the hydroxylation of NT in a highly enantioselective manner to (-)-E-10-OH-NT in the liver. Another P450 isozyme besides IID6 seems to be responsible for the formation of the (+)-enantiomer in the liver. In intestinal homogenate, the formation of both enantiomers of E-10-OH-NT was inhibited to about the same extent by quinidine, the maximum inhibition being much less than in the liver. In the urine of six patients treated with NT, the (-)-enantiomer accounted for 91 +/- 2% of the unconjugated E-10-OH-NT, and for 78 +/- 6% of the glucuronide conjugates. The study shows that NT is hydroxylated in a highly enantioselective way, probably catalyzed by the polymorphic P450IID6, to (-)-E-10-OH-NT both in vitro in human liver as well as in vivo in patients treated with the drug.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Glucuronates / urine
  • Humans
  • Hydroxylation
  • Intestinal Mucosa / metabolism*
  • Microsomes, Liver / metabolism*
  • NADP / metabolism
  • Nortriptyline / analogs & derivatives
  • Nortriptyline / metabolism*
  • Nortriptyline / therapeutic use
  • Nortriptyline / urine
  • Quinine / pharmacology
  • Stereoisomerism


  • Glucuronates
  • 10-hydroxynortriptyline
  • NADP
  • Quinine
  • Nortriptyline