Clinical Relevance of P-Glycoprotein in Drug Therapy

Abstract

The drug efflux transporter P-glycoprotein (P-gp) is known to confer multidrug resistance in cancer chemotherapy. The P-gp is highly expressed in many types of tumor cells, as well as many normal tissues, including the apical surface of intestinal epithelial cells, and the luminal surface of capillary endothelial cells in the brain. Because of its expression and localization, it has been suggested that P-gp plays an important role in cancer chemotherapy, intestinal absorption, and brain uptake. This review addresses the significance of the role of P-gp in cancer chemotherapy, drug absorption, and brain uptake. Based on the clinical and animal studies with P-gp modulators, it has become apparent that the role of P-gp in multidrug resistance is far less important compared to other biological factors. Although P-gp is highly expressed in both intestinal epithelial cells and endothelial cells of brain capillaries and functions as an efflux transporter in both organs, the magnitude of P-gp's impact on intestinal absorption and brain uptake of drugs is quantitatively very different. From animal and clinical studies, it is evident that P-gp plays a very important role in CNS penetration of drugs, whereas the effect of P-gp on drug absorption is not as important as generally believed.

Prediction of human pharmacokinetics—biliary and intestinal clearance and enterohepatic circulation

“…CL i values are low, and approximately 10, 20 and 0.2% of the MDR1 substrates digoxin and talinolol and BCRP substrate rosuvastatin (MW 482 g mol −1 ), respectively, is secreted by the human small intestine (colonic secretion and reabsorption not considered) (Gramatté & Oertel 1999;Greiner et al 1999;Drescher et al 2003;Lin & Yamazaki 2003;Bergman et al 2006;Lennernäs 2007). These findings are in agreement with the absence of MDR1, MRP2 and BCRP in basolateral enterocyte membranes, low Q in the intestinal mucosa compared with the liver and kidneys (~1/6 to ~1/5) and (anticipated) limited amount/fraction of enterocytes involved.…”

Modest Effect of Impaired P-glycoprotein on the Plasma Concentrations of Fexofenadine, Quinidine, and Loperamide following Oral Administration in Collies

“…These changes have been accounted for by modulation of P-gp activity in the small intestine, inhibition, or induction. Apart from these drugs, the effect of P-gp on drug absorption in humans remains under question since some clinically important drugs have been developed as oral formulations even though they are P-gp substrates (Lin and Yamazaki, 2003).…”

Antigenic Epitopes on Human P-glycoprotein Recognized by Autoimmune Hepatitis Autoantibody as a Case Study

“…An experiment with mdr1 gene knockout mice showed the high plasma area under the curve (AUC) of drugs in mdr null mice [mdr1a(−/−)] and a high level in the brain, indicating that mdr1 has an efflux function (prevention of absorption) in the intestinal lumen and acts as a drug uptake barrier in the brain, as well as having the function of urinary and biliary drugs excretion. [21][22][23] The transcription of MDR1 is dependent on two sites, the promoter site (−105/−100)(−245/−141) and the enhancer site (−7864/−7817). 24,25) The rough three-dimensional structure of MDR1 with a resolution of 8Å was reported and the transmembrane regions adopted an asymetric configuration in the nucleotide-bound state.…”