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Drug Metabolism and Disposition Fast Forward
First published on January 14, 2008; DOI: 10.1124/dmd.107.019448

0090-9556/08/3604-740-744$20.00
DMD 36:740-744, 2008

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Role of the Multidrug Transporter Proteins ABCB1 and ABCC2 in the Diaplacental Transport of Talinolol in the Term Human Placenta

Karen May, Veronika Minarikova, Knud Linnemann, Marek Zygmunt, Heyo K. Kroemer, Christoph Fusch, and Werner Siegmund

Departments of Clinical Pharmacology (K.M., V.M., W.S.), Pharmacology (H.K.K.), Gynecology and Obstetrics (M.Z.), and Neonatology and Pediatric Intensive Care (K.L., C.F.), University of Greifswald, Greifswald, Germany

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.

Address correspondence to: Werner Siegmund, Department of Clinical Pharmacology, Ernst Moritz Arndt University, Friedrich-Loeffler-Str. 23d, D-17487 Greifswald, Germany. E-mail: siegmuw{at}uni-greifswald.de






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