In vitro assessment of the roles of drug transporters in the disposition and drug-drug interaction potential of olaparib.
1. In vitro assessments were conducted to examine interactions between olaparib (a potent oral inhibitor of poly[ADP-ribose] polymerase) and drug transporters. 2. Olaparib showed inhibition of the hepatic drug uptake transporters OATP1B1 (IC50values of 20.3 μM and 27.1 μM) and OCT1 (IC5037.9 μM), but limited inhibition of OATP1B3 (25% at 100 μM); inhibition of the renal uptake transporters OCT2 (IC5019.9 μM) and OAT3 (IC5018.4 μM), but limited inhibition of OAT1 (13.5% at 100 μM); inhibition of the renal efflux transporters MATE1 and MATE2K (IC50s 5.50 μM and 47.1 μM, respectively); inhibition of the efflux transporter MDR1 (IC5076.0 μM), but limited inhibition of BCRP (47% at 100 μM) and no inhibition of MRP2. At clinically relevant exposures, olaparib has the potential to cause pharmacokinetic interactions via inhibition of OCT1, OCT2, OATP1B1, OAT3, MATE1 and MATE2K in the liver and kidney, as well as MDR1 in the liver and GI tract. Olaparib was found to be a substrate of MDR1 but not of several other transporters. 3. Our assessments indicate that olaparib is a substrate of MDR1 and may cause clinically meaningful inhibition of MDR1, OCT1, OCT2, OATP1B1, OAT3, MATE1 and MATE2K.
a DMPK Consulting UK Ltd , Congleton , UK and.
Alex
A
McCormick
b Therakin Consulting , Sandbach , UK.
Helen
H
Swaisland
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D001692:Biological Transport; D004347:Drug Interactions; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1 / Q000378:metabolism; D010793:Phthalazines / Q000378:metabolism*; D010879:Piperazines / Q000378:metabolism*
D000970:Antineoplastic Agents; D027381:Liver-Specific Organic Anion Transporter 1; D010793:Phthalazines; D010879:Piperazines; C531550:olaparib
Drug interaction; MATE; MDR; OAT; OATP; OCT; drug transporter; olaparib