MRP Transporters

The MRP (Multidrug Resistance Protein) family of the ABCC subfamily covers several transporters with distinct tissue distributions, substrate specificities, and regulatory relevance. Knowing which MRP matters for your drug candidate — and in which tissue — determines which vesicle kit you need and when. This guide maps each MRP to its clinical context.

The MRP family — overview

MRP transporters are ATP-binding cassette (ABC) efflux transporters that move substrates out of cells — often against concentration gradients. They transport organic anions, conjugated metabolites (glucuronides, sulfates, glutathione conjugates), and drugs. Their clinical relevance spans three areas: drug-drug interaction (DDI) risk, hepatotoxicity (particularly cholestasis for MRP2), and multi-drug resistance in oncology.

Which MRP do regulators require?

FDA (Drug Interaction Studies Guidance 2020) and EMA (Guideline on the investigation of drug interactions 2012, updated 2024) give specific guidance on which transporters require in vitro assessment before IND/NDA/MAA submission:

MRP2 — required for all hepatically cleared drugs

MRP2 (ABCC2) is expressed at the canalicular membrane of hepatocytes — it exports drugs and conjugated metabolites from hepatocytes into bile. Inhibition of MRP2 by a co-administered drug can reduce biliary excretion of MRP2 substrates, increasing their systemic exposure (DDI) or causing intrahepatic accumulation (cholestasis risk). FDA and EMA both specify MRP2 as a transporter that should be assessed when hepatic elimination is the primary clearance route or when cholestatic DILI is a concern.

MRP1 — required for oncology drugs

MRP1 is the primary mediator of MDR in small cell lung cancer, breast cancer, and haematological malignancies. For oncology drugs, EMA guidance specifically mentions MRP1 as a transporter whose inhibition potential should be characterised — particularly when the drug targets cancer types where MRP1-driven resistance is documented.

MRP3 and MRP4 — emerging regulatory interest

MRP3 and MRP4 are increasingly mentioned in FDA correspondence for drugs with hepatotoxicity signals or with primary renal elimination. They are not universally required but should be assessed when there is a mechanistic reason to suspect their involvement.

Which SeamlessBio vesicle kit to use

Vesicle assay format — how it works

All MRP vesicle assays use the same inside-out membrane vesicle format: membrane vesicles are prepared from cells overexpressing the target MRP, inverted so that the intracellular face is on the outside. ATP is added to drive active transport — the substrate accumulates inside the vesicle. Rapid filtration stops the reaction; accumulated substrate is measured by scintillation counting (radiolabelled substrate) or LC-MS/MS. Transport activity is expressed as the ratio of substrate accumulated in MRP-expressing vesicles vs matched control vesicles (overexpressing an empty vector).

The assay answers two questions: is your compound an MRP substrate? and does your compound inhibit MRP-mediated transport of a known substrate (DDI liability)?