2.6. Transporter Models

Drug transporters are intrinsic membrane proteins that facilitate the passage of xenobiotics and endogenous substances across the many biological membranes found in mammalian tissues, thereby playing a rate-limiting role in the intestinal absorption (the "A" in ADMET) and the distribution (the "D" in ADMET) of many drug molecules between and within tissues such as the intestine, liver, kidney and brain. In particular, those that catalyze efflux can reduce net absorption whereas those that catalyze uptake can enhance absorption.

The most pharmacologically important transporters are necessarily somewhat non-selective by nature, which provides opportunities for their various substrates to interfere with each other's transport to a greater or lesser extent - i.e., opportunities for drug-drug interactions, or DDIs. A drug that inhibits an intestinal efflux transporter may cause blood levels of substrates for that transporter to rise when co-administered with them, for example. Administering an inducer of such an efflux transporter, on the other hand, will depress the net intestinal absorption of its substrates. The earlier such adverse drug-drug interaction (DDIs) can be identified in a drug development program, the better.

Transporters are distributed throughout the body. Most transporters of pharmaceutical interest that belong to the solute-linked carrier (SLC) gene family catalyze carrier-mediated uptake, whereas most that catalyze efflux belong to the ATP-binding cassette (ABC) gene family. The Transporter Module provides models for nine transporters that are responsible for most DDIs:

Organic anion transport polypeptides 1B1 (OATP1B1; SLCo1B1) and 1B3 (OATP1B3; SLCo1B3) catalyze uptake across the basolateral membrane of liver cells. Notable substrates include statins, sartans and glucuronides.
Organic anion transporters 1 (OAT1; SLC22A6) and 3 (OAT3; SLC22A8) catalyze uptake across the basolateral membranes of kidney cells, where they are responsible for removing their substrates from the circulation. Notable substrates include antivirals, antibiotics and some statins.
Organic cation transporter 1 (OCT1; SLC22A1) also catalyzes uptake across the basolateral membrane of liver cells. Prominent substrates include metformin, pentamidine and acyclovir.
OCT2 (SLC22A2), on the other hand, catalyzes uptake across the basolateral membrane of kidney cells and is found on the brain side of the blood-brain barrier. Its substrates include ranitidine and cimetidine.
The efflux transporter P-gp (which stands for permeability glycoprotein) is the translation product of the multidrug resistance gene MDR1, which is also known by its more systematic designation, ABCB1. It and the efflux transporter BCRP (breast cancer resistance protein; ABCG2) pump their substrates out of kidney, liver and intestinal cells as well as the cells that make up the blood-brain barrier into the urine, bile, gut and blood, respectively. Hence they have played key roles in absorption and excretion, by way of which they affect bioavailability and toxicology. As one might guess from their names, both are involved in tumor resistance.
The bile salt export pump (BSEP; ABCB11) is found in the liver, where it is responsible for pumping bile salts into the bile canaliculus. The main pharmacological concern is that inhibition of that transport can lead to liver injury due to the resulting accumulation of bile salts.

The FDA, EMA, and PMDA strongly recommend comprehensively profiling interactions between these major transporters and any new drug candidate to identify cases where it could play the role of either victim (as a substrate) or perpetrator (inhibitor) in potential DDI with drugs already on the market.

The Transporters Module introduced in ADMET Predictor 10.0 allows you to estimate the likelihood that a compound is a substrate or inhibitor of one of these key transporters. It also provides regression models for predicting the corresponding affinities (i.e., Michaelis constants, or K_M's) for the uptake transporters. Affinity models for efflux transporters are not provided because the data necessary to construct them is much more difficult to obtain. Basically, they would need to reflect concentrations within assayed cells, which are generally not amenable to experimental manipulation.