Prediction of clinical drug-drug interactions of veliparib (ABT-888) with human renal transporters (OAT1, OAT3, OCT2, MATE1, and MATE2K).
J Pharm Sci
; 102(12): 4426-32, 2013 Dec.
Article
en En
| MEDLINE
| ID: mdl-24122511
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Bencimidazoles
/
Transportadores de Anión Orgánico Sodio-Independiente
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Proteínas de Transporte de Catión Orgánico
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Riñón
Tipo de estudio:
Prognostic_studies
/
Risk_factors_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
J Pharm Sci
Año:
2013
Tipo del documento:
Article