Efflux transporter P-glycoprotein

Retina-to-blood efflux transport P-Glycoprotein (mdr 1 a) Cyclosporin A and others + TR-iBRB [14,19, 45, 53, 54]... 

Teft WA et al (2011) Endoxifen, the active metabolite of tamoxifen, is a substrate of the efflux transporter P-glycoprotein (multidrug resistance 1). Drug Metab Dispos 39 558-562... 

The blood-brain barrier is a biochemical as well as a physical barrier. Brain endothelial cells create an enzymatic barrier composed of secreted proteases and nucleotidases, as well as intracellular metabolizing enzymes such as cytochrome P-450. Furthermore, y-glutamyl transpeptidase, alkaline phosphatase, and aromatic acid decarboxylase are more prevalent in cerebral microvessels than in nonneuronal capillaries. The efflux transporter P-glycoprotein and other extrusion pumps are present on the membrane surface of endothelial cells, juxtaposed toward the interior of the capillary. Furthermore, CNS endothelial cells display a net negative charge at the interior of the capillaries and at the basement membrane. This provides an additional selective mechanism by impeding passage of anionic molecules across the membrane. 

However, drug substances for which /a may be affected by active transport processes [e.g., the efflux transporter P-glycoprotein (P-gp)] may require further model characterization to prevent misclassification of their permeability class. For example, functional expression of efflux transporters must be determined in cultured human or animal epithelial monolayers. At this time, the FDA recommends limiting the use of non-human permeability test methods to drug substances whose absorption is controlled by passive mechanisms. When applying the BCS, an apparent passive mechanism may be inferred when one of the following conditions is satisfied (i) a linear pharmacokinetic relationship between dose and a measure of bioavailability (e.g., area under the plasma concentration-time curve, AUC) is demonstrated in humans ... 

The efflux transporter P-glycoprotein (P-gp) has been proposed as a potential therapeutic target for AD [439]. Approximately 10-35 % decrease in 125I-Ap(i 0) intracellular accumulation was observed in cells treated with rifampicin, dexamethasone, caffeine, verapamil, hyperforin, p-estradiol, and pentylenetetrazole, drugs known to induce P-gp expression [439],... 

Efflux transporter P-glycoprotein (P-gp) at the BBB restricts substrate compounds from entering the brain and may thus contribute to pharmacoresistance in CNS disorders, cancer, and brain... 

Benedetti, M. S., Whomsley, R., Espie, P., and Baltes, E. (2004) The role of the efflux transporter P-glycoprotein (P-gp) on the disposition of antiepileptic drugs implications for drug interactions. In Focus on Epilepsy Research, Benjamin Shawn, M., (ed.), Nova Science, New York, pp. 199-220. 

Fexofenadine, the carboxylic acid metabolite of terfenadine, is widely available (Fig. 37.13). It accounts for the antihistaminic properties of terfenadine, which is very rapidly metabolized via CYP3A4-catalyzed processes. Members of the organic anion transporter protein family and the drug efflux transporter P-glycoprotein are involved in the disposition of fexofenadine. Fexofenadine does not have the antiarrhythmic side effects of terfenadine. 

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