Utility of Mdr1-gene deficient mice in assessing the impact of P-glycoprotein on pharmacokinetics and pharmacodynamics in drug discovery and development.

Since the generation of the multi-drug resistance 1 (mdr1) gene knockout (KO) mice in the early 90's, these animals have been instrumental to our understanding of the physiological roles of mdr1 gene product P-glycoprotein. Located in crucial organs such as brain, intestine, liver, and kidney, P-glycoprotein-mediated transport has been shown to affect both the pharmacokinetics and pharmacodynamics of endogenous compounds and xenobiotics. It appears that P-glycoprotein may not be essential for the maintenance of normal body function as suggested by the similarity in life span and serum chemistry values of mdr1 gene KO mice compared to their genetically competent littermates. However, numerous studies have demonstrated that P-glycoprotein limits the brain penetration of many drug substrates. The reduced central nervous system (CNS) access of these compounds has been linked to decreased pharmacological or toxicological effects. In contrast to the critical role that P-glycoprotein plays in the brain, the extent of P-glycoprotein involvement in oral absorption and hepatobiliary or renal excretion of xenobiotics appears more variable. In addition to the mdr1 gene KO model, in vitro cell lines that over-express P-glycoprotein, and clinical trials using P-glycoprotein modulators have allowed for the comparison of in vitro-in vivo and species related difference in P-glycoprotein activity. For the most part, studies have shown reasonable in vitro-in vivo correlations, modest species-related differences, and comparable human-mouse in vivo P-glycoprotein effects on systemic drug disposition. Therefore, the mdr1 gene KO mouse model, when used appropriately, may allow for prediction of CNS drug access and certain drug-drug interaction.