In vitro assessment of the roles of drug transporters in the disposition and drug–drug interaction potential of olaparib

Abstract

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 (IC₅₀ values of 20.3 μM and 27.1 μM) and OCT1 (IC₅₀ 37.9 μM), but limited inhibition of OATP1B3 (25% at 100 μM); inhibition of the renal uptake transporters OCT2 (IC₅₀ 19.9 μM) and OAT3 (IC₅₀ 18.4 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 (IC₅₀ 76.0 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.

Keywords:

• Drug interaction
• drug transporter
• MATE
• MDR
• OAT
• OATP
• OCT
• olaparib

Acknowledgements

This work was supported by AstraZeneca. The authors would like to acknowledge Glynis Nichols PhD and Robert Elsby PhD (both former AZ employees) who were involved in experimental design, experimental conduct and data interpretation. This study was sponsored by AstraZeneca. Medical writing assistance was provided by Claire Routley PhD from Mudskipper Business Ltd, funded by AstraZeneca.

Declaration of interest

The authors were employees of AstraZeneca at the time of the study and hold stock in AstraZeneca.