Efflux by P-glycoprotein

FIG. 2 Mechanisms of drug transfer in the cellular layers that line different compartments in the body. These mechanisms regulate drug absorption, distribution, and elimination. The figure illustrates these mechanisms in the intestinal wall. (1) Passive transcellular diffusion across the lipid bilayers, (2) paracellular passive diffusion, (3) efflux by P-glycoprotein, (4) metabolism during drug absorption, (5) active transport, and (6) transcytosis [251]. 

Decreased production or mutation of TOPO-1 can cause resistance to the cytotoxic effects of topotecan and other CPTs active efflux of TPT by P-glycoprotein-mediated transport might also contribute to resistance. 

Takanaga H, Ohnishi A, Matsuo H, Sawada Y. Inhibition of vinblastine efflux mediated by P-glycoprotein by grapefruit juice components in caco-2 cells. Biol Pharm Bull 1998 21(10) 1062 1066. 

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. 

Drugs in this class are well absorbed but their bioavailability may be limited either by first-pass metabolism or by P-glycoprotein-mediated efflux from the intestinal mucosa. In vitro-in vivo correlations of dissolution rate with the rate of drug absorption are expected if dissociation is slower than gastric emptying rate. If dissociation is sufficiently rapid, gastric emptying will limit absorption rate. 

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 ... 

Renal tubular dysfunction is described in animals but human expression in unclear [12]. Most use of mTOR inhibitors is in conjunction with lowered doses of calcineurin inhibitors since it is known that these two drug classes have a potent drug-drug interaction leading to enhanced renal dysfunction compared to the calcineurin inhibitor alone [782]. This may be explained by inhibition of drug efflux pump P-glycoprotein since both siroiimus and the calcineurin inhibitors are competitive substrates [783, 784]. 

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