It doesn't work because the effects fall off with tissue concentration. Here is another reason that it may not work. Here are P-glycoprotein expressing cells, AR10. We have done it with two or three different ones, and now this is the index of tissue penetration. I have taken out the bare membrane, and this is showing, and I am sorry these colors don't show up very well, that this is the wild-type cell.
Penetration is poor.
P-glycoprotein inhibitors, yes, they may allow more drug uptake in cells proximal to blood vessels, but they also markedly decrease penetration, another reason why that probably hasn't worked. We are not interested really though in why things haven't worked. What we would like to do is to delineate properties that are amenable to modification, and I think this is amenable to modification. We have shown we can do that, say, for standard ways of inhibiting methotrexate uptake. We have shown that P-glycoprotein will do that, but that is not really likely to improve therapeutic index.