Clomipramine N-demethylation metabolism in human liver microsomes

Zhongguo Yao Li Xue Bao. 1998 Sep;19(5):433-6.

Abstract

Aim: To study the effect of cytochrome P-450 (CYP450) inhibitors on clomipramine (Clo) N-demethylation in vitro.

Methods: The kinetic parameters of Clo N-demethylation in human liver microsomes were obtained by the Michaelis-Menten equation. The parameters after pretreatment with putative inhibitors of various CYP450 isoforms were compared with controls.

Results: K(m1), K(m2), Vmax1, Vmax2, Vmax1/K(m1), and Vmax2/K(m2) were (0.11 +/- 0.06), (24 +/- 14) mumol.L-1, (114 +/- 47), (428 +/- 188) nmol.g-1.min-1, (1.8 +/- 1.6), and (0.019 +/- 0.005) L.g-1.min-1, respectively. The interindividual variations for the last 4 parameters reached up to 2.5-, 7.3-, 3.4-, and 1.8-fold. At 5 mumol.L-1 of Clo, troleandomycin (Tro), furafylline (Fur), ditiocarb sodium (Dit), and S-mephenytoin (Mep) produced a marked inhibition on Clo N-demethylation while sulfaphenazole (Sul) and quinidine (Qui) had only slight effects. The inhibitory rates by Dit 30, Mep 500, Fur 10, Tro 10, Fur 80, Tro 200 and Fur 80 + Tro 200 mumol.L-1 were 27.0%, 32.9%, 42.8%, 40.5%, 63.9%, 66.4%, and 78.3%, respectively. The IC50 (95% confidence limits) for Fur and Tro were 27.7 (19.1-36.3) and 42.1 (20.9-63.3) mumol.L-1, respectively.

Conclusions: The N-demethylation of Clo exhibited a biphasic behavior. This reaction was mediated mainly by both CYP1A2 and CYP3A4, to a minor extent by CYP2C19 at the low concentration of Clo in vitro.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Clomipramine / metabolism*
  • Cytochrome P-450 CYP1A2 Inhibitors
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors
  • Humans
  • In Vitro Techniques
  • Mephenytoin / pharmacology
  • Methylation
  • Microsomes, Liver / metabolism*
  • Middle Aged
  • Mixed Function Oxygenases / antagonists & inhibitors
  • Theophylline / analogs & derivatives
  • Theophylline / pharmacology
  • Troleandomycin / pharmacology

Substances

  • Cytochrome P-450 CYP1A2 Inhibitors
  • Cytochrome P-450 Enzyme Inhibitors
  • Theophylline
  • furafylline
  • Troleandomycin
  • Mixed Function Oxygenases
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Clomipramine
  • Mephenytoin