title: The use of microdialysis techniques in mice to study P-gp function at the blood-brain barrier.
abstract: An integrated assay system involving dual/triple-probe microdialysis techniques in rats was developed earlier for testing interactions with P-glycoprotein (P-gp) at the blood-brain barrier using quinidine/PSC-833 as a P-gp substrate/inhibitor combination. The aim of the present study was to expand our assay system to mice using microdialysis with simultaneous sampling of blood and brain and to compare the result with a primary mouse brain endothelial cell monolayer (pMBMEC) assay. Brain penetration of quinidine was dose dependent in both anesthetized and awake mice after intraperitoneal drug administration. PSC-833 pretreatment caused a 2.5- to 3.4-fold increase in quinidine levels of brain dialysate samples in anesthetized or awake animals, after single or repeated administration of PSC-833. In pMBMEC, a 2.0- to 2.5-fold efflux ratio was observed in the transcellular transport of quinidine. The P-gp-mediated vectorial transport of quinidine was eliminated by PSC-833. These results indicate that quinidine with PSC-833 is a good probe substrate-reference inhibitor combination for testing drug-drug interactions with P-gp in the in vivo and in vitro mouse systems. With increasing number of humanized transgenic mice, a test system with mouse microdialysis experimentation becomes more important to predict drug-drug interactions in humans.
authors.affiliation: Solvo Biotechnology, Szeged, Hungary. sziraki@solvo.com
authors.forename: István
authors.initials: I
authors.lastname: Sziráki
authors.forename: Franciska
authors.initials: F
authors.lastname: Erdő
authors.forename: Péter
authors.initials: P
authors.lastname: Trampus
authors.forename: Mirabella
authors.initials: M
authors.lastname: Sike
authors.forename: Petra Magdolna
authors.initials: PM
authors.lastname: Molnár
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Rajnai
authors.forename: Judit
authors.initials: J
authors.lastname: Molnár
authors.forename: Imola
authors.initials: I
authors.lastname: Wilhelm
authors.forename: Csilla
authors.initials: C
authors.lastname: Fazakas
authors.forename: Emese
authors.initials: E
authors.lastname: Kis
authors.forename: István
authors.initials: I
authors.lastname: Krizbai
authors.forename: Péter
authors.initials: P
authors.lastname: Krajcsi
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000758:Anesthesia; D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002478:Cells, Cultured; D003524:Cyclosporins / Q000378:metabolism; D004347:Drug Interactions; D042783:Endothelial Cells / Q000378:metabolism; D005240:Feasibility Studies; D006801:Humans; D008297:Male; D051379:Mice; D017551:Microdialysis / Q000379:methods*; D011802:Quinidine / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D013379:Substrate Specificity; D013997:Time Factors
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003524:Cyclosporins; D011802:Quinidine; C070272:valspodar