FULL BLOCKADE OF INTESTINAL P-GLYCOPROTEIN AND EXTENSIVE INHIBITION OF BLOOD-BRAIN-BARRIER P-GLYCOPROTEIN BY ORAL TREATMENT OF MICE WITH PSC833

Mice lacking mdr1-type P-glycoproteins (mdr1a/1b [-/-] mice) display l arge changes in the pharmacokinetics of digoxin and other drugs. Using the kinetics of digoxin in mdr1a/1b (-/-) mice as a model representin g a complete block of P-glycoprotein activity, we investigated the act ivity and specificity of the reversal agent SDZ PSC833 in inhibiting m dr1-type P-glycoproteins in vivo, Oral PSC833 was coadministered with intravenous [H-3]digoxin to wild-type and mdr1a/1b (-/-) mice, The dir ect excretion of [3H]digoxin mediated by P-glycoprotein in the intesti nal mucosa of wild-type mice was abolished by administration of PSC833 , Hepatobiliary excretion of [H-3]digoxin was markedly decreased in bo th wild-type and mdr1a/1b (-/-) mice by PSC833, the latter effect indi cating that in vivo, PSC833 inhibits not only mdr1-type P-glycoprotein s, but also other drug transporters. Upon coadministration of PSC833, brain levels of [H-3]digoxin in wild-type mice showed a large increase , approaching (but not equaling) the levels found in brains of PSC833- treated mdr1a/1b (-/-) mice. Thus, orally administered PSC833 can inhi bit blood-brain barrier P-glycoprotein extensively, and intestinal P-g lycoprotein completely, These profound pharmacokinetic effects of PSC8 33 treatment imply potential risks, but also promising pharmacological applications of the use of effective reversal agents.