Capturing the applicability of in vitro-in silico membrane transporter data in chemical risk assessment and biomedical research

Abstract

Costs, scientific and ethical concerns related to animal tests for regulatory decision-making have stimulated the development of alternative methods. When applying alternative approaches, kinetics have been identified as a key element to consider. Membrane transporters affect the kinetic processes of absorption, distribution, metabolism and excretion (ADME) of various compounds, such as drugs or environmental chemicals. Therefore, pharmaceutical scientists have intensively studied transporters impacting drug efficacy and safety. Besides pharmacokinetics, transporters are considered as major determinant of toxicokinetics, potentially representing an essential piece of information in chemical risk assessment. To capture the applicability of transporter data for kinetic-based risk assessment in non-pharmaceutical sectors, the EU Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) created a survey with a view of identifying the improvements needed when using in vitro and in silico methods.Seventy-three participants, from different sectors and with various kinds of expertise, completed the survey. The results revealed that transporters are investigated mainly during drug development, but also for risk assessment purposes of food and feed contaminants, industrial chemicals, cosmetics, nanomaterials and in the context of environmental toxicology, by applying both in vitro and in silico tools. However, to rely only on alternative methods for chemical risk assessment, it is critical that the data generated by in vitro and in silico methods are scientific integer, reproducible and of high quality so that they are trusted by decision makers and used by industry. In line, the respondents identified various challenges related to the interpretation and use of transporter data from non-animal methods. Overall, it was determined that a combined mechanistically-anchored in vitro-in silico approach, validated against available human data, would gain confidence in using transporter data within an animal-free risk assessment paradigm. Finally, respondents involved primarily in fundamental research expressed lower confidence in non-animal studies to unravel complex transporter mechanisms.

Next generation physiologically based kinetic (NG-PBK) models in support of regulatory decision making

“…Membrane transporters influence the ADME processes of various endogenous and exogenous compounds [25] , [54] . In recent decades, the pharmaceutical field has placed considerable effort into the study of transporters affecting drug disposition, therapeutic efficacy, and adverse outcomes, but little is known in regards to transporter effects on environmental chemicals [15] . Transporters can play a significant role in chemical distribution.…”

“…Transporters can play a significant role in chemical distribution. As such, integration of membrane transporter-based experimental data during parameterization of several types of computational models (e.g., QSAR, pharmacophore, and PBK models), through use of platforms like SimCyp, PKSim, or GastroPlus, will enable better understanding of chemical/drug disposition [15] .…”

Membrane transporter data to support kinetically-informed chemical risk assessment using non-animal methods: Scientific and regulatory perspectives

“…Even if the in vivo relevance of chemical-transporter interactions remains to be clearly demonstrated, transporter kinetic data can still be applied for CRA purposes, such as improving in vitro to in vivo extrapolation (IVIVE), better characterising in vitro toxicological assays, or prioritising further assessments (Clerbaux et al, 2018).…”

“…However, how the existing knowledge on drug transporters could be applied to CRA is not yet fully understood. In a first attempt to capture the current state-of-play and challenges in the application of in vitro and in silico methods to study transporters for CRA purposes, we created a survey that was disseminated among transporter experts (Clerbaux et al, 2018). A key finding of the survey was that transporters are being investigated primarily during drug development, but also for CRA purposes of food and feed contaminants, industrial chemicals, cosmetics, nanomaterials and in the context of environmental toxicology, by applying both in vitro and in silico tools.…”

Neonicotinoid pesticides poorly interact with human drug transporters

“…Drugs are not only substrates for these transporters but may also act as inhibitors, which may cause drug‐drug interactions through altered pharmacokinetics of coadministrated drugs, or adverse effects through impaired transport of endogenous substrates . Besides drugs, environmental pollutants, including pesticides, interact with drug transporters, thus underlining interest in studying potential transporter‐chemical interactions in an extensive and detailed manner . Some pyrethroid insecticides, organophosphorus compounds or organochlorine pesticides thus inhibit activity of ABC and/or SLC drug transporters, whereas other pesticides, like the insecticide methoxychlor or the herbicide 2,4‐dichlorophenoxyacetic acid are substrates for transporters.…”