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Cytochrome P450 3A4 is the major enzyme responsible for the metabolism of laquinimod, a novel immunomodulator

Tuvesson, Helen LU ; Hallin, I; Persson, R; Sparre, B; Gunnarsson, P O and Seidegård, Janeric (2005) In Drug Metabolism and Disposition 33(6). p.866-872
Abstract
In the present study, the involvement of cytochrome P450 enzyme( s) in the primary metabolism of laquinimod, a new orally active immunomodulator, has been investigated in human liver microsomes. Hydroxylated and dealkylated metabolites were formed. The metabolite formation exhibited single enzyme Michaelis-Menten kinetics with apparent K-M in the range of 0.09 to 1.9 mM and V-max from 22 to 120 pmol/mg/min. A strong correlation between the formation rate of metabolites and 6β-hydroxylation of testosterone was obtained within a panel of liver microsomes from 15 individuals (r(2) = 0.6 to 0.94). Moreover, ketoconazole and troleandomycin, specific inhibitors of CYP3A4 metabolism, demonstrated a significant inhibition of laquinimod metabolism.... (More)
In the present study, the involvement of cytochrome P450 enzyme( s) in the primary metabolism of laquinimod, a new orally active immunomodulator, has been investigated in human liver microsomes. Hydroxylated and dealkylated metabolites were formed. The metabolite formation exhibited single enzyme Michaelis-Menten kinetics with apparent K-M in the range of 0.09 to 1.9 mM and V-max from 22 to 120 pmol/mg/min. A strong correlation between the formation rate of metabolites and 6β-hydroxylation of testosterone was obtained within a panel of liver microsomes from 15 individuals (r(2) = 0.6 to 0.94). Moreover, ketoconazole and troleandomycin, specific inhibitors of CYP3A4 metabolism, demonstrated a significant inhibition of laquinimod metabolism. Furthermore, in incubations with recombinant CYP3A4, all the primary metabolites were formed. In vitro interaction studies with CYP3A4 substrates and possible concomitant medication demonstrated that laquinimod inhibits the metabolism of ethinyl estradiol with an IC50 value of about 150 μ M, which is high above the plasma level of laquinimod after clinically relevant doses. Ketoconazole, troleandomycin, erythromycin, prednisolone, and ethinyl estradiol inhibited the metabolism of laquinimod, and IC50 values of 0.2, 11, 24, 87, and 235 μ M, respectively, were calculated. In conclusion, the present study demonstrates that laquinimod is a low affinity substrate for CYP3A4 in human liver microsomes. The likelihood for in vivo effects of laquinimod on the metabolism of other CYP3A4 substrates is minor. However, inhibitory effects on the metabolism of laquinimod by potent and specific inhibitors of CYP3A4, such as ketoconazole, are anticipated and should be considered in the continued clinical program for laquinimod. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Drug Metabolism and Disposition
volume
33
issue
6
pages
866 - 872
publisher
American Society for Pharmacology and Experimental Therapeutics
external identifiers
  • wos:000229138100023
  • pmid:15764719
  • scopus:18844434431
ISSN
1521-009X
DOI
10.1124/dmd.104.002238
language
English
LU publication?
yes
id
c5c6dd8e-f864-4cc5-a4fb-c1f64bace628 (old id 240271)
date added to LUP
2007-08-08 09:56:07
date last changed
2017-01-01 04:56:09
@article{c5c6dd8e-f864-4cc5-a4fb-c1f64bace628,
  abstract     = {In the present study, the involvement of cytochrome P450 enzyme( s) in the primary metabolism of laquinimod, a new orally active immunomodulator, has been investigated in human liver microsomes. Hydroxylated and dealkylated metabolites were formed. The metabolite formation exhibited single enzyme Michaelis-Menten kinetics with apparent K-M in the range of 0.09 to 1.9 mM and V-max from 22 to 120 pmol/mg/min. A strong correlation between the formation rate of metabolites and 6β-hydroxylation of testosterone was obtained within a panel of liver microsomes from 15 individuals (r(2) = 0.6 to 0.94). Moreover, ketoconazole and troleandomycin, specific inhibitors of CYP3A4 metabolism, demonstrated a significant inhibition of laquinimod metabolism. Furthermore, in incubations with recombinant CYP3A4, all the primary metabolites were formed. In vitro interaction studies with CYP3A4 substrates and possible concomitant medication demonstrated that laquinimod inhibits the metabolism of ethinyl estradiol with an IC50 value of about 150 μ M, which is high above the plasma level of laquinimod after clinically relevant doses. Ketoconazole, troleandomycin, erythromycin, prednisolone, and ethinyl estradiol inhibited the metabolism of laquinimod, and IC50 values of 0.2, 11, 24, 87, and 235 μ M, respectively, were calculated. In conclusion, the present study demonstrates that laquinimod is a low affinity substrate for CYP3A4 in human liver microsomes. The likelihood for in vivo effects of laquinimod on the metabolism of other CYP3A4 substrates is minor. However, inhibitory effects on the metabolism of laquinimod by potent and specific inhibitors of CYP3A4, such as ketoconazole, are anticipated and should be considered in the continued clinical program for laquinimod.},
  author       = {Tuvesson, Helen and Hallin, I and Persson, R and Sparre, B and Gunnarsson, P O and Seidegård, Janeric},
  issn         = {1521-009X},
  language     = {eng},
  number       = {6},
  pages        = {866--872},
  publisher    = {American Society for Pharmacology and Experimental Therapeutics},
  series       = {Drug Metabolism and Disposition},
  title        = {Cytochrome P450 3A4 is the major enzyme responsible for the metabolism of laquinimod, a novel immunomodulator},
  url          = {http://dx.doi.org/10.1124/dmd.104.002238},
  volume       = {33},
  year         = {2005},
}