The Center for Alternatives to Animal Testing is an academic center affiliated with the Division of Toxicological Sciences in the Department of Environmental Health Sciences of the Johns Hopkins University Bloomberg School of Public Health.

 

Johns Hopkins School of Public Health

Abstract for TestSmart--Pharmaceuticals: An Efficient and Humane Approach to Predictors of Potential Toxic Effects of Drugs

Multi-drug Resistant Gene Knockout Model

Diane Umbenhauer
Merck

Drug transporters are now recognized as important contributors to drug uptake, distribution and elimination. The most widely studied transporter family is P-glycoprotein (Pgp), a cell efflux pump located generally in tissue interfaces such as the intestine, brain capillaries and placenta, as well as liver and kidney. P-glycoproteins are encoded by the multidrug resistant gene (mdr) family. Much of our knowledge regarding the physiological role of the P-glycoproteins has been gained through animal models that are deficient in one or more specific Pgps. These models include targeted knockout mice as well as a naturally occurring genetic knockout model.

Studies with these animal models have established the important role of Pgp in barrier tissues such as the blood-brain barrier and placenta. They have been used to determine whether there is a physiological role for these transporters in specific drug effects, either an intended therapeutic effect or an unwanted toxic effect. For example, mdr1a -/- mice are deficient in Pgp in the microvessel endothelial cells that make up the blood-brain barrier. When these mice are treated with Pgp substrates such as ivermectin or loperamide, the brain drug levels are much higher than normal, resulting in greatly increased sensitivity of the -/- animals to the neurotoxicity induced by these drugs.

Mouse fetuses that are mdr1a -/- have placentae that are deficient in Pgp. This placental Pgp deficiency compromises the maternal-fetal barrier, leading to higher fetal ivermectin exposure and the generation of cleft palate during development in the -/- fetuses. Most importantly, these animal models have dramatically raised our awareness of a role that Pgp plays in drug distribution and therefore in both toxicity and efficacy failure, especially for CNS targets. The result of this increased awareness is the development of in vitro models to predict whether a compound is a substrate and/or inhibitor early in the drug development process. The in vivo models can therefore be extremely useful along with the in vitro models to determine the potential involvement of Pgp in drug uptake and distribution and their relationship to toxicity or efficacy.