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Therapeutic implications of the MDR‐1 gene
Author(s) -
Mealey K. L.
Publication year - 2004
Publication title -
journal of veterinary pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.527
H-Index - 60
eISSN - 1365-2885
pISSN - 0140-7783
DOI - 10.1111/j.1365-2885.2004.00607.x
Subject(s) - pharmacology , pharmacokinetics , p glycoprotein , ivermectin , drug , atp binding cassette transporter , biology , medicine , transporter , pharmacodynamics , gene , drug resistance , multiple drug resistance , genetics , zoology
Drug transporters significantly influence drug pharmacokinetics and pharmacodynamics. P‐glycoprotein (P‐gp), the product of the MDR1 (ABCB1) gene, is among the most well‐characterized drug transporters, particularly in veterinary medicine. A number of clinically relevant, structurally and functionally unrelated drugs are substrates for P‐gp. P‐gp is expressed by a variety of normal tissues including the intestines, renal tubular cells, brain capillary endothelial cells, biliary canalicular cells, and others, where it functions to actively extrude substrate drugs. In this capacity, P‐gp limits oral absorption and central nervous system entry of many substrate drugs. A number of MDR1 polymorphisms have been described in human patients, some of which result in altered drug pharmacokinetics and susceptibility to diseases such as Parkinson's disease, inflammatory bowel disease, refractory seizures, and others. An MDR1 polymorphism in herding breed dogs, including collies and Australian shepherds, has been demonstrated to be the cause of ivermectin sensitivity in these breeds. Recent evidence suggests that this polymorphism, a 4‐bp deletion mutation, results in increased susceptibility to the toxicity of several drugs in addition to ivermectin. Furthermore, data in rodent models suggest that P‐gp may play an important role in regulating the hypothalamic–pituitary–adrenal axis.