PT  - JOURNAL ARTICLE
AU  - Helén Tuvesson
AU  - Ingrid Hallin
AU  - Robert Persson
AU  - Birgitta Sparre
AU  - Per Olov Gunnarsson
AU  - Janeric Seidegård
TI  - CYTOCHROME P450 3A4 IS THE MAJOR ENZYME RESPONSIBLE FOR THE METABOLISM OF LAQUINIMOD, A NOVEL IMMUNOMODULATOR
AID  - 10.1124/dmd.104.002238
DP  - 2005 Jun 01
TA  - Drug Metabolism and Disposition
PG  - 866--872
VI  - 33
IP  - 6
4099  - http://dmd.aspetjournals.org/content/33/6/866.short
4100  - http://dmd.aspetjournals.org/content/33/6/866.full
SO  - Drug Metab Dispos2005 Jun 01; 33
AB  - 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 KM in the range of 0.09 to 1.9 mM and Vmax 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 (r2 = 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 μM, 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 μM, 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. The American Society for Pharmacology and Experimental Therapeutics