title: Placental passage of olomoucine II, but not purvalanol A, is affected by p-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2) and multidrug resistance-associated proteins (ABCCs).
abstract: 1. Purine cyclin-dependent kinase inhibitors have recently been recognised as promising candidates for the treatment of various cancers. While pharmacodynamic properties of these compounds are relatively well understood, their pharmacokinetics including possible interactions with placental transport systems have not been characterised to date. 2. In this study, we investigated transplacental passage of olomoucine II and purvalanol A in rat focusing on possible role of p-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2) and/or multidrug resistance-associated proteins (ABCCs). Employing the in situ method of dually perfused rat term placenta, we demonstrate transplacental passage of both olomoucine II and purvalanol A against the concentration gradient in foetus-to-mother direction. Using several ATP-binding cassette (ABC) drug transporter inhibitors, we confirm the participation of ABCB1, ABCG2 and ABCCs transporters in the placental passage of olomoucine II, but not purvalanol A. 3. Transplacental passage of olomoucine II and purvalanol A from mother to foetus is significantly reduced by active transporters, restricting thereby foetal exposure and providing protection against harmful effects of these xenobiotics. Importantly, we demonstrate that in spite of their considerable structural similarity, the two molecules utilise distinct placental transport systems. These facts should be kept in mind when introducing these prospective anticancer candidates and/or their analogues into the clinical area.
authors.affiliation: a Department of Pharmacology and Toxicology and.
authors.forename: Jakub
authors.initials: J
authors.lastname: Hofman
authors.affiliation: b Department of Pharmaceutical Chemistry and Drug Analysis, Faculty of Pharmacy in Hradec Kralove , Charles University in Prague , Hradec Kralove , Czech Republic.
authors.forename: Radim
authors.initials: R
authors.lastname: Kučera
authors.affiliation: a Department of Pharmacology and Toxicology and.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Neumanova
authors.affiliation: b Department of Pharmaceutical Chemistry and Drug Analysis, Faculty of Pharmacy in Hradec Kralove , Charles University in Prague , Hradec Kralove , Czech Republic.
authors.forename: Jiri
authors.initials: J
authors.lastname: Klimes
authors.affiliation: a Department of Pharmacology and Toxicology and.
authors.forename: Martina
authors.initials: M
authors.lastname: Ceckova
authors.affiliation: a Department of Pharmacology and Toxicology and.
authors.forename: Frantisek
authors.initials: F
authors.lastname: Staud
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D001693:Biological Transport, Active; D002851:Chromatography, High Pressure Liquid; D005260:Female; D018811:Maternal Exposure; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D010920:Placenta / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy; D011270:Pregnancy, Animal; D011687:Purines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D000077546:Roscovitine; D014327:Trophoblasts / Q000187:drug effects; D015262:Xenobiotics / Q000737:chemistry
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011687:Purines; D000077546:Roscovitine; D015262:Xenobiotics; C471843:6-((3-chloro)anilino)-2-(isopropyl-2-hydroxyethylamino)-9-isopropylpurine; C489249:Abcg2 protein, rat; C475587:olomoucine II; C095122:multidrug resistance protein 3
keywords: Cyclin-dependent kinase inhibitors; drug efflux transporters; olomoucine II; placental pharmacokinetics; purvalanol A