title: Prediction of clinical drug-drug interactions of veliparib (ABT-888) with human renal transporters (OAT1, OAT3, OCT2, MATE1, and MATE2K).
abstract: Veliparib (ABT-888) is largely eliminated as parent drug in human urine (70% of the dose). Renal unbound clearance exceeds glomerular filtration rate, suggesting the involvement of transporter-mediated active secretion. Clinically relevant pharmacokinetic interactions in the kidney have been associated with OAT1, OAT3, OCT2, MATE1, and MATE2K. In the present study, interactions of veliparib with these transporters were investigated. Veliparib inhibited OAT1, OAT3, OCT2, MATE1, and MATE2K with IC50 values of 1371, 505, 3913, 69.9, and 69.5 μM, respectively. The clinical unbound maximum plasma concentration of veliparib after single oral dose of 50 mg (0.45 μM) is manyfold lower than IC50 values for OAT1, OAT3, OCT2, MATE1, or MATE2K. These results indicate a low potential for drug-drug interaction (DDI) with OAT1/3, OCT2, or MATE1/2K. Additional studies demonstrated that veliparib is a substrate of OCT2. In Oct1/Oct2 double-knockout mice, the plasma exposure of veliparib was increased by 1.5-fold, and the renal clearance was decreased by 1.8-fold as compared with wild-type mice, demonstrating that organic cation transporters contribute to the renal elimination in vivo. In summary, the in vitro transporter data for veliparib predicts minimal potential for an OAT1/3-, OCT2-, and MATE1/2K-mediated DDI given the clinical exposure after single oral dose of 50 mg.
authors.affiliation: Drug Metabolism and Pharmacokinetics, AbbVie Inc, North Chicago, Illinois 60064.
authors.forename: Ryota
authors.initials: R
authors.lastname: Kikuchi
authors.forename: Yanbin
authors.initials: Y
authors.lastname: Lao
authors.forename: Daniel A J
authors.initials: DA
authors.lastname: Bow
authors.forename: William J
authors.initials: WJ
authors.lastname: Chiou
authors.forename: Mark E
authors.initials: ME
authors.lastname: Andracki
authors.forename: Robert A
authors.initials: RA
authors.lastname: Carr
authors.forename: Richard L
authors.initials: RL
authors.lastname: Voorman
authors.forename: Sonia M
authors.initials: SM
authors.lastname: De Morais
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics*; D002460:Cell Line; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors / Q000378:metabolism*; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D001562:Benzimidazoles; D029362:Organic Anion Transporters, Sodium-Independent; D027701:Organic Cation Transport Proteins; C521013:veliparib
keywords: drug interaction; drug transport; membrane transporters; organic anion transporters; organic cation transporters; renal clearance; renal transport; veliparib