title: In vitro evaluation of the interaction potential of irosustat with drug-metabolizing enzymes.
abstract: Irosustat is a first-generation, irreversible, steroid sulfatase inhibitor currently in development for hormone-dependent cancer therapy. To predict clinical drug-drug interactions between irosustat and possible concomitantly administered medications, the inhibition/induction potential of irosustat with the main drug-metabolizing enzymes was investigated in vitro. The interaction of aromatase inhibitors in the in vitro metabolism of irosustat was also studied. Irosustat inhibited CYP1A2 activity in human liver microsomes through the formation of its desulfamoylated degradation product and metabolite 667-coumarin. CYP1A2 inhibition by 667-coumarin was competitive, with a K(i) of 0.77 μM, a concentration exceeding by only 5-fold the maximal steady-state concentration of 667-coumarin in human plasma with the recommended dose of irosustat. In addition, 667-coumarin metabolites enhanced the inhibition of CYP1A2 activity. Additional clinical interaction studies of irosustat with CYP1A2 substrate drugs are strongly recommended. 667-Coumarin also appeared to be a competitive inhibitor of CYP2C19 (K(i) = 5.8 μM) in human liver microsomes, and this inhibition increased with assessment in human hepatocytes. Inhibition of CYP2C19 enzyme activity was not caused by repression of CYP2C19 gene expression. Therefore, additional mechanistic experiments or follow-up studies with clinical evaluation are recommended. Irosustat neither inhibited CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6, CYP2E1, CYP3A4/5, or UDP-glucuronosyltransferase 1A1, 1A4, or 2B7 activities nor induced CYP1A2, CYP2C9, CYP2C19, or CYP3A4/5 at clinically relevant concentrations. Results from human liver microsomes indicated that no changes in irosustat pharmacokinetics in vivo are expected as a result of inhibition of irosustat metabolism in cases of concomitant medication administration or irosustat-aromatase inhibitor combination therapy with letrozole, anastrozole, or exemestane.
authors.affiliation: Pharmacokinetics and Drug Metabolism Department, Ipsen Pharma, Barcelona, Spain.
authors.forename: Verònica
authors.initials: V
authors.lastname: Ventura
authors.forename: Josep
authors.initials: J
authors.lastname: Solà
authors.forename: Concepción
authors.initials: C
authors.lastname: Peraire
authors.forename: Françoise
authors.initials: F
authors.lastname: Brée
authors.forename: Rosendo
authors.initials: R
authors.lastname: Obach
mesh_terms: D047072:Aromatase Inhibitors / Q000378:metabolism / Q000494:pharmacology; D003374:Coumarins / Q000378:metabolism / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004347:Drug Interactions; D005260:Female; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D007527:Isoenzymes; D008862:Microsomes, Liver / Q000201:enzymology* / Q000378:metabolism*; D013451:Sulfonic Acids / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D047072:Aromatase Inhibitors; D003374:Coumarins; D065607:Cytochrome P-450 Enzyme Inhibitors; D007527:Isoenzymes; D013451:Sulfonic Acids; C520511:irosustat; D003577:Cytochrome P-450 Enzyme System; C030123:coumarin; D014453:Glucuronosyltransferase