The FDA and EMA each recommend a battery of ADME-related properties to be examined in preclinical drug development, including CYP and non-CYP enzymes, and more recently transporters. These guidelines (which have been summarised in our free guide) aim to improve the safety of clinical trial participants and patients, as well as reduce the risk of late-stage attrition due to drug-drug interactions (DDIs). One of the tests involved in assessing clinical DDI risk assessment involves evaluating whether or not a drug inhibits transporters in vitro, which is based on determination of a compound’s IC50, and then putting this data into context with therapeutic dose. For this reason it is critical that the in vitro derivation of the IC50 (or Ki) parameter results in a value that is an accurate representation of the in vivo situation.
Our recent research in the field of drug transporters investigated whether an inhibitor pre-incubation step with the main human solute carrier (SLC) transporters (OATP1B1, OAT3, OCT2, MATE1), prior to the usual methodology of co-incubation of inhibitor with transported probe substrate, would impact IC50 values of prototypical inhibitors. First, the optimal pre-incubation time was determined using an OATP1B1-expressing cell line. Based on these results, experiments were also performed in OAT3, OCT2 and MATE1-expressing cells. The results indicate that the impact of an inhibitor pre-incubation step on inhibitory effects (IC50 values) may be transporter-specific, with some transporters being susceptible to changes in IC50 and others showing no effect. At the moment it’s still too soon to determine whether these results will be applicable to all inhibitors of a particular transporter or translate to the clinic, and we are currently undertaking further research to understand this. However, for certain SLC transporters, it seems as though pre-incubating cells with inhibitor as part of a standard inhibition assay could provide a more accurate in vitro parameter for prediction of clinical DDI risk.
To learn more about this research, please download our poster, recently presented by Cyprotex’s Drug Transporter Team Leader, Rob Elsby, PhD at the AAPS/ITC Joint Workshop in Baltimore, MD, USA in April 2015: