Impact of enzalutamide and its main metabolite <i>N</i>‐desmethyl enzalutamide on pharmacokinetically important drug metabolizing enzymes and drug transporters

<jats:title>Abstract</jats:title><jats:p>Enzalutamide is a new drug against castration‐resistant prostate cancer. Recent data indicate profound induction of drug metabolizing enzymes (e.g. cytochrome P450 isoenzyme (CYP) 3A4) but comprehensive in vitro data on other CYP enzymes, drug conjugating enzymes or drug transporters is scarce. Moreover, the mechanisms of induction are poorly investigated and the effects of the active metabolite <jats:italic>N</jats:italic>‐desmethyl enzalutamide are unknown. Using LS180 cells as an induction model and quantitative real‐time reverse transcription polymerase chain reaction, our study demonstrated a concentration‐dependent induction of <jats:italic>CYP1A1, CYP1A2, CYP3A5, CYP3A4, UGT1A3, UGT1A9, ABCB1, ABCC2</jats:italic> and <jats:italic>ABCG2</jats:italic> mRNA. Induction of CYP3A4 and ABCB1 was confirmed by Western blot analysis and is likely mediated by activation of the nuclear receptor pregnane x receptor, elucidated by a luciferase‐based reporter gene assay. Enzalutamide's main active metabolite <jats:italic>N</jats:italic>‐desmethyl enzalutamide exhibited only weak induction properties. mRNA expression of <jats:italic>UGT2B7</jats:italic> was suppressed by enzalutamide and its metabolite. Both compounds are apparently not transported by P‐glycoprotein (P‐gp) or breast cancer resistance protein (BCRP). <jats:italic>N</jats:italic>‐desmethyl enzalutamide more potently inhibited important drug transporters (P‐gp, BCRP, OATPs) than enzalutamide. Taken together, the pharmacokinetics of concurrently administered drugs is likely altered during enzalutamide therapy. Levels of metabolically (mainly CYP3A4) eliminated drugs are expected to be decreased, whereas the abundance of compounds with solely transporter‐determined pharmacokinetics (P‐gp, OATPs) is likely enhanced.</jats:p>