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

Abstract

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 N-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 CYP1A1, CYP1A2, CYP3A5, CYP3A4, UGT1A3, UGT1A9, ABCB1, ABCC2 and ABCG2 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 N-desmethyl enzalutamide exhibited only weak induction properties. mRNA expression of UGT2B7 was suppressed by enzalutamide and its metabolite. Both compounds are apparently not transported by P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP). N-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.

Herb–Drug Interaction Potential of Anti-Borreliae Effective Extracts from Uncaria tomentosa (Samento) and Otoba parvifolia (Banderol) Assessed In Vitro

“…For induction experiments, the human colon adenocarcinoma cell line LS180 (available at ATCC, Manassas, VA, USA) was used. This cell line is a suitable surrogate for the intestine being a major site of drug interactions and it is ideal for investigating AhR and PXR mediated induction [27]. Cells were cultured under standard cell culture conditions as published previously [27].…”

“…For UGT1A3 a Quantitect Kit (Qiagen, Hilden, Germany) was used according to the manufacturer’s instructions and primers for CYP2J2 were published by another group [29]. All other primer sequences and PCR conditions were published previously [27].…”

Enzalutamide Versus Abiraterone as a First-Line Endocrine Therapy for Castration-Resistant Prostate Cancer: Protocol for a Multicenter Randomized Phase 3 Trial

“…Moreover, enzalutamide exhibits induction effects on CYP3A4, CYP2C9, CYP2C19, CYP2B6, uridine diphosphate-glucuronyltransferase, and P-glycoprotein. It exhibits inhibitory activity against P-glycoprotein, breast cancer-resistance protein, organic cation transporter 1, and organic anion transporter 3 [ 9 ]. Due to the long elimination half-life (4.7-8.4 days), enzalutamide may still induce or inhibit metabolic enzymes and transporters after completion of treatment.…”

RP-HPLC-UV Method for Simultaneous Quantification of Second Generation Non-Steroidal Antiandrogens Along with their Active Metabolites in Mice Plasma: Application to a Pharmacokinetic Study

“…The validated HPLC method was successfully applied to a pharmacokinetic study in mice. potency to enzalutamide [12,13]. Darolutamide (ODM-201; ▶Fig.…”