Permeability glycoprotein

In this situation, cell lines are shown to be resistant to colchicine, doxorubicin, vinblastine, and actinomycin D. This syndrome is accompanied by an increase in measurable membrane glycoprotein (the P-170 or permeability glycoprotein). It is believed that this protein transports hydrophobic chemicals out of cells and thereby prevents drug action. Current efforts to inhibit this efferent transport protein are currently underway but, sadly, have to date been largely unsuccessful (i5). 

Zoghhi, S.S., How, J.S., Yasuno, F., Hong, J., Tuan, E., Lazarova, N., Gladding, R.L., Pike, V.W and Irmis, R.B. (2008) IIC-loperamide and its N-desmethyl radiometahohte are avid substrates for brain permeability-glycoprotein efflux. Journal of Nuclear Medicine, 49, 649-656. 

Plasmodium falciparum Trypanosoma congolense Trypanosoma cruzi low density lipoprotein calcium ATPase multiple sclerosis Human immunodeficiency vims Staphylococcus aureus epigallocatechin-3-gallate permeability glycoprotein Cytochrome P450 3A4... 

D. J., Jeffrey, P. Improving the in vitro prediction of in vivo centtal nervous system penetration Integrating permeability, P-glycoprotein efflux, and free fractions in blood and brain. 

Dudley, A., Beliveau, R. P-glycoprotein deficient mouse in situ blood-brain barrier permeability and its predicfion using an in comho PAM PA model, (under review)... 

J Riordan, V Ling. (1979). Purification of P-glycoprotein from plasma membrane vesicles of Chinese hamster ovary cell mutants with reduced colchicine permeability. J Biol Chem 254 12701-12705. 

In conclusion, there are several drawbacks to the use of Caco-2 cells in studies of active drug transport. Despite these drawbacks, we note that a recent comprehensive study comparing various P-glycoprotein drug efflux assays in drug discovery came to the conclusion that the Caco-2 transport assay is the method of choice, since it displays a biased responsiveness towards compounds with low or moderate permeability - in other words, towards compounds whose intestinal permeability is most likely to be significantly affected by drug efflux mechanisms [101]. 

Collett, A., Higgs, N. B., Sims, E., Rowland, M., Warhurst, G., Modulation of the permeability of H2 receptor antagonists cimetidine and ranitidine by P-glycoprotein in rat intestine and the human colonic cell line Caco-2, J. Pharmacol. Exp. Ther. 1999, 288, 171-178. 

Li, L. Y., Amidon, G. L., Kim, J. S., Heimbach, T.j Kesisoglou, F. et al., Intestinal metabolism promotes regional differences in apical uptake of indinavir coupled effect of P-glycoprotein and cytochrome P450 3A on indinavir membrane permeability in rat, /. Pharmacol. Exp. Ther. 2002, 301, 586-593. 

Juliano, R. L., Ling, V., A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants, Biochim. Biophys. Acta 1976, 455, 152-162. 

The use of Caco-2 cell monolayers has gained in popularity as an in vivo human absorption surrogate moreover, the monolayers are generally accepted as a primary absorption screening tool by several pharmaceutical companies [10]. However, Caco-2 cell permeability measurements exhibit certain limitations due to the mechanisms involved. Both passive and active pathways exist active transport tends to increase the absorption across the cells and, since Caco-2 cells overexpress the P-glycoprotein (P-gp) efflux pump, the absorption of some compounds across these cells may be underestimated. 

J. E., Influence of passive permeability on apparent P-glycoprotein kinetics, Pharm. Res. 2000, 37, 1456-1460. 

Rao W, Dahlheimer JL, Bardgett ME, Snyder AZ, Finch RA, Sartorelli AC et al. Choroid plexus epithelial expression of MDR1 P glycoprotein and multidmg resistance-associated protein contribute to the blood-cerebrospinalfluid drug-permeability barrier. Proc Natl Acad Sci USA 1999 96(7) 3900-3905. 

In a study of p-glycoprotein substrates vs. non-substrates, Varma et al. [48] concluded that substrate molecules with high passive permeability overwhelmed the transporter while substrate molecules with moderate passive permeability were more affected by p-glycoprotein. Approximately half of 63 p-glycoprotein substrates studied had MW >400 and PSA > 75 indicating that larger, more polar molecules are more likely to be p-glycoprotein substrates. 

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