Transporters play an important role in drug pharmacokinetics and pharmacodynamics. The FDA recognizes this and as a result, they recommend testing new drug candidates for transporter interactions.
Much like Cytochrome P450 enzymes, which are ubiquitously expressed throughout the body, but are in greatest abundance in the liver, transporters can also be found throughout the body. They are highly expressed along the blood-brain barrier, liver canalicular and basolateral membranes, intestinal epithelium and in the renal proximal tubules. Although there are many known transporters, there is a focus on the following human transporters: OAT1, OAT3, OCT2, MATE1, MATE2K, BSEP, Pg-p, and BCRP. It is important to know whether new drug candidates are substrates, inhibitors, or inducers of these important proteins. Transporters can control the intracellular concentration of drugs in the liver and kidneys, influence absorption across the intestinal epithelium, and movement into the brain. Uptake and efflux transporters are located in many important areas of the body, and as such, can significantly impact drug kinetics as well as the kinetics of other drugs.
Intestinal transporters on the apical and basolateral membrane can impact drug movement into the body.
Uptake and Efflux Transporters in the Blood-Brain Barrier Microcapillary
Transporters located on the Hepatic Apical and Basolateral Membrane of the Liver.
To evaluate drug-transporter interactions, IONTOX utilizes HEK human embryonic kidney cells stably transfected with key transporters (TransportoCellsTM). See figure 1 below.
In addition to transfected HEK cells, IONTOX has a license to work with a renal line derived from normal human proximal tubular cells (CiPTEC) that express high levels of key transporters. An example of OCT2 inhibition is shown in the figure below. ASP is a substrate specific to this transporter, and by measuring a test compound’s impact on the uptake of ASP, it is possible to generate inhibition curved and Michaelis-Menten kinetic parameters. Whether looking at renal, hepatic or intestinal transporter interaction, standard probe substrates are used for positive controls and for historical performance of the assays.
Figure 1. Example of TransportoCell for OATP1B1 Inhibition Assay
Figure 2. Inhibition of OCT2 in a Human Renal Cell Line Derived from Normal Tissues
IC50 for inhibition and development of kinetic parameters provides important information for understanding potential DDIs.
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