Membrane transporters – pharmacokinetic interaction

Membrane transporters – pharmacokinetic interaction refers to the processes by which drugs interact with membrane-bound proteins, significantly impacting their absorption, distribution, metabolism, and excretion (ADME) (FDA, 2020 [https://www.fda.gov/regulatory-information/search-fda-guidance-documents/vitro-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions]). These transporters are categorized into two main superfamilies: the ATP-Binding Cassette (ABC) transporters, such as P-glycoprotein (P-gp/ABCB1), and the Solute Carrier (SLC) transporters, such as Organic Anion Transporting Polypeptides (OATPs) (International Transporter Consortium, 2010 [https://doi.org/10.1038/nrd3028]). Interactions occur when a drug serves as a substrate, inhibitor, or inducer of these proteins, which can lead to clinically significant drug-drug interactions (DDIs) (Giacomini et al., 2010 [https://pubmed.ncbi.nlm.nih.gov/20168317/]). For example, inhibition of OATP1B1 by drugs like cyclosporine can increase the plasma concentration of statins, raising the risk of myopathy (Hillgren et al., 2013 [https://pubmed.ncbi.nlm.nih.gov/23531503/]). These interactions are critical in drug development for predicting safety profiles and determining dosage adjustments in polypharmacy scenarios. Consequently, regulatory agencies require extensive screening of new molecular entities against a panel of key transporters to mitigate risks of toxicity or therapeutic failure (EMA, 2012 [https://www.ema.europa.eu/en/medicines/scientific-guidelines/investigation-drug-interactions]).

Other names

Transporter-mediated drug-drug interactionsMembrane transporter interactionsTransporter-mediated pharmacokineticsDrug-transporter interactionsTransporter-mediated ADME

Competitive or non-competitive inhibition, or transcriptional induction of membrane transport proteins, leading to altered substrate flux across biological membranes and changes in systemic drug exposure.