Role of the multidrug transporter proteins ABCB1 and ABCC2 in the diaplacental transport of talinolol in the term human placenta.
Placental syncytiotrophoblasts are known to express the efflux transporter proteins P-glycoprotein (ABCB1) and multidrug resistance-associated protein 2 (ABCC2), which are supposed to be a functional part of the human placental barrier. With advancing gestational age, expression of ABCB1 decreases progressively, whereas ABCC2 is more expressed. To evaluate to which extent they contribute to placental barrier function at term, permeability of talinolol, a substrate of both carriers, was measured using a validated human placenta perfusion model. We identified in randomized, crossover experiments a unidirectional transfer of talinolol in the fetomaternal direction because the maternofetal transfer was significantly lower (0.663 +/- 0.188 versus 0.394 +/- 0.067 relative to creatinine permeability, p = 0.012). Maternofetal permeability was increased by the ABCC2 inhibitor probenecid (0.59 +/- 0.15 versus 0.68 +/- 0.13, p = 0.028) and the nonspecific inhibitor verapamil (0.53 +/- 0.09 versus 0.66 +/- 0.16, p = 0.028) but was not influenced by the ABCB1 inhibitor valspodar (PSC833) (0.48 +/- 0.11 versus 0.46 +/- 0.09, p = 0.345). Genetic polymorphisms of ABCB1 and ABCC2 lacked significant influence on expression of the carriers and permeability of talinolol, respectively. In conclusion, maternofetal transfer of talinolol is restricted by a unidirectional process that is influenced by inhibitors of ABCC2.
May
Karen
K
Department of Clinical Pharmacology, University of Greifswald, Greifswald, Germany.
Minarikova
Veronika
V
Linnemann
Knud
K
Zygmunt
Marek
M
Kroemer
Heyo K
HK
Fusch
Christoph
C
Siegmund
Werner
W
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism* / Q000502:physiology; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D018592:Cross-Over Studies; D005260:Female; D006801:Humans; D008431:Maternal-Fetal Exchange / Q000187:drug effects / Q000502:physiology; D026901:Membrane Transport Proteins / Q000378:metabolism* / Q000502:physiology; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism* / Q000502:physiology; D010920:Placenta / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy; D011412:Propanolamines / Q000378:metabolism* / Q000494:pharmacology
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011412:Propanolamines; C513055:ABCB1 protein, human; C000715087:ABCC2 protein, human; C011550:talinolol