title: Quinidine as an ABCB1 probe for testing drug interactions at the blood-brain barrier: an in vitro in vivo correlation study.
abstract: This study provides evidence that quinidine can be used as a probe substrate for ABCB1 in multiple experimental systems both in vitro and in vivo relevant to the blood-brain barrier (BBB). The combination of quinidine and PSC-833 (valspodar) is an effective tool to assess investigational drugs for interactions on ABCB1. Effects of quinidine and substrate-inhibitor interactions were tested in a membrane assay and in monolayer assays. The authors compared quinidine and digoxin as ABCB1 probes in the in vitro assays and found that quinidine was more potent and at least as specific as digoxin in ATPase and monolayer efflux assays employing MDCKII-MDR1 and the rat brain microcapillary endothelial cell system. Brain exposure to quinidine was tested in dual-/triple-probe microdialysis experiments in rats by assessing levels of quinidine in blood and brain. Comparing quinidine levels in dialysate samples from valspodar-treated and control animals, it is evident that systemic/local administration of the inhibitor diminishes the pumping function of ABCB1 at the BBB, resulting in an increased brain penetration of quinidine. In sum, quinidine is a good probe to study ABCB1 function at the BBB. Moreover, quinidine/PSC-833 is an ABCB1-specific substrate/inhibitor combination applicable to many assay systems both in vitro and in vivo.
authors.affiliation: Laboratory of Microdialysis, Solvo Biotechnology, Berlini u. 47-49, Budapest, Hungary. sziraki@solvo.com
authors.forename: István
authors.initials: I
authors.lastname: Sziráki
authors.forename: Franciska
authors.initials: F
authors.lastname: Erdo
authors.forename: Erzsébet
authors.initials: E
authors.lastname: Beéry
authors.forename: Petra Magdolna
authors.initials: PM
authors.lastname: Molnár
authors.forename: Csilla
authors.initials: C
authors.lastname: Fazakas
authors.forename: Imola
authors.initials: I
authors.lastname: Wilhelm
authors.forename: Ildikó
authors.initials: I
authors.lastname: Makai
authors.forename: Emese
authors.initials: E
authors.lastname: Kis
authors.forename: Krisztina
authors.initials: K
authors.lastname: Herédi-Szabó
authors.forename: Tibor
authors.initials: T
authors.lastname: Abonyi
authors.forename: István
authors.initials: I
authors.lastname: Krizbai
authors.forename: Gábor K
authors.initials: GK
authors.lastname: Tóth
authors.forename: Péter
authors.initials: P
authors.lastname: Krajcsi
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001688:Biological Products / Q000032:analysis; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D018920:Coculture Techniques; D003524:Cyclosporins / Q000494:pharmacology; D004077:Digoxin / Q000494:pharmacology; D004285:Dogs; D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004347:Drug Interactions; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D057166:High-Throughput Screening Assays; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008297:Male; D017551:Microdialysis; D011802:Quinidine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D001688:Biological Products; D003524:Cyclosporins; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D004077:Digoxin; C095122:multidrug resistance protein 3; D011802:Quinidine; C070272:valspodar