title: Full blockade of intestinal P-glycoprotein and extensive inhibition of blood-brain barrier P-glycoprotein by oral treatment of mice with PSC833.
abstract: Mice lacking mdr1-type P-glycoproteins (mdr1a/1b [-/-] mice) display large changes in the pharmacokinetics of digoxin and other drugs. Using the kinetics of digoxin in mdr1a/1b (-/-) mice as a model representing a complete block of P-glycoprotein activity, we investigated the activity and specificity of the reversal agent SDZ PSC833 in inhibiting mdr1-type P-glycoproteins in vivo. Oral PSC833 was coadministered with intravenous [3H]digoxin to wild-type and mdr1a/1b (-/-) mice. The direct excretion of [3H]digoxin mediated by P-glycoprotein in the intestinal mucosa of wild-type mice was abolished by administration of PSC833. Hepatobiliary excretion of [3H]digoxin was markedly decreased in both wild-type and mdr1a/1b (-/-) mice by PSC833, the latter effect indicating that in vivo, PSC833 inhibits not only mdr1-type P-glycoproteins, but also other drug transporters. Upon coadministration of PSC833, brain levels of [3H]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 inhibit blood-brain barrier P-glycoprotein extensively, and intestinal P-glycoprotein completely. These profound pharmacokinetic effects of PSC833 treatment imply potential risks, but also promising pharmacological applications of the use of effective reversal agents.
authors.affiliation: Division of Molecular Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: U
authors.initials: U
authors.lastname: Mayer
authors.forename: E
authors.initials: E
authors.lastname: Wagenaar
authors.forename: B
authors.initials: B
authors.lastname: Dorobek
authors.forename: J H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: P
authors.initials: P
authors.lastname: Borst
authors.forename: A H
authors.initials: AH
authors.lastname: Schinkel
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000172:deficiency*; D000284:Administration, Oral; D000818:Animals; D001646:Bile / Q000187:drug effects / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000378:metabolism*; D003524:Cyclosporins / Q000008:administration & dosage / Q000494:pharmacology*; D004077:Digoxin / Q000097:blood / Q000493:pharmacokinetics*; D018432:Drug Resistance, Multiple; D005766:Gastrointestinal Contents / Q000737:chemistry*; D007422:Intestines / Q000187:drug effects / Q000502:physiology; D008099:Liver / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003524:Cyclosporins; D004077:Digoxin; C070272:valspodar