SOLVO Drug Transporter Assay Services

The interaction of drug candidates with specific drug transporters involved in mediating their absorption, disposition, metabolism, elimination, and toxicity (ADMET) profiles could result in clinical effects ranging from loss of efficacy, compromised safety, poor pharmacokinetics, and adverse pharmacodynamics. Global regulatory agencies therefore expect new drug applications to include extensive in vitro transporter data covering the interactions of drug candidates with drug transporters as an integral part of the risk assessment for the optimal use of therapies in targeted patient populations. In addition to drug-drug interaction (DDI) liability, investigation on modulation of transporters that govern the transport of endogenous compounds or tissue distribution of drugs could impact safety or efficacy beyond the systemic level.

Charles River now offers the broadest array, representing the full range of transporter services and products to test drug-transporter interactions, transporter-mediated drug-drug interactions, and transporter-mediated toxicity through its acquisition of SOLVO Biotechnology.

Understanding the role that drug transporters play in drug disposition can provide a significant insight into drug discovery and development strategies as well as help elucidate emerging associated research areas like transporter biomarkers, assessment and modulation of tissue concentrations, and effect of diseases on transporter expression and function.

When are drug transporter assays needed?

Every program is unique, but a thoughtful strategy is driven by your clinical plan and should consist of three phases from early discovery to post-marketing drug labelling.

Scientists must carefully plan and execute assays for drug transporters via multi-well plates as the majority of drugs interact with transporter proteins as substrates and/or inhibitors and can be a critical step in determining a drug’s ADMET profile and derisking a candidate prior to development.

  1. The first phase of a top-notch drug transporters strategy is from discovery to the first-in-human (FIH). Here, researchers should review the therapeutic area, patient population, potential co-medications, routes of administration, and drug development plan. Based on this information, some early transporter screens for broad specificity drug transporters and those involved in disposition of likely co-medications should be considered to support lead optimization and de-risking of candidate molecules prior to entry into the clinic.
  2. FIH to proof-of-concept (POC) is the second phase where the role of drug transporters in the ADME properties of a drug and its potential drug-drug interactions are investigated. Inhibition studies are run for clinically-relevant transporters, with additional transporter substrate assessments carried out to help further develop a transporter strategy.
  3. The final phase from POC to a New Drug Application (NDA) and marketing is aimed at translating the collected knowledge and data into drug labeling advice.

Commonly used methods

Although there are many in vitro methods to study the wide range of membrane transporters, the most commonly used methods are vesicular transport assays, uptake assays in transfected cell lines, and bidirectional transport assays in polarized cell lines.

Your assay choice depends on the questions you need to address and the physicochemical properties of your compound, with each assay having distinct advantages and disadvantages. Use of optimized and validated drug transporter assays during drug discovery and development leads to greater confidence. With a well thought out strategy one can improve assay reproducibility and allow drug transporter assays to define if a test compound is substrate or inhibitor of uptake and efflux transporters.

Assay Method Summary
Vesicular Transport Suitable for efflux transporter inhibition studies using all permeability classes of compound, and substrate studies with low permeability compounds. Cell-free system, which can be used to evaluate cytotoxic compounds
Recombinant cell lines expressing uptake transporters Investigates activity of a single transporter, i.e., the preferred method to study uptake transporter inhibition and substrate activity
Bidirectional transport assays in polarized cell monolayers For efflux transporter substrate studies with medium-high permeability

Regulatory guidance documents

The FDA, EMA, and PMDA have all issued guidance documents to help drug researchers meet the expectations of regulatory agencies to evaluate drug-drug interaction potential of investigational new drugs. Our scientists have decades of experience in designing and choosing the most relevant in vitro experimental systems, conditions, and model-based DDI strategies with metabolizing enzymes and transporters in accordance with these guidelines.

European Medicines Agency (EMA): Investigation of Drug Interactions
U.S. Food and Drug Administration (FDA): In Vitro Metabolism – and Transporter-Mediated Drug-Drug Interaction Studies Guidance for Industry

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Frequently Asked Questions (FAQs) about Assays for Drug Transporters

  • What are drug transporters?

    Drug transporters are proteins that can mediate the movement (uptake or efflux transporters) of drugs across cellular membranes and as a result can have an impact on the pharmacokinetics of both endogenous and xenobiotic compounds. The majority of clinically significant membrane transport proteins can be split into two families: the uptake transporters or solute-linked carrier (SLC) family and the efflux transporters or ATP-binding cassette (ABC) family. The effect of these transporters on drug pharmacokinetics has moved them to the forefront of pharmaceutical research and in vitro drug transporter assays help investigate if newly-developed drugs interact with these proteins, either directly as transported substrates, or as inhibitors which can modulate the disposition of co-administered compounds.

  • What is a drug-drug interaction?

    A drug-drug interaction (DDI) occurs when the administration of one drug modifies the pharmacokinetics, pharmacodynamics, or disposition of another drug. A DDI can delay, decrease, or enhance the ADMET profile of either drug, which in turn can cause an adverse effect on the efficacy or toxicity profile of one or both drugs.