Drug Design, Development and Therapy (Dec 2018)
The role of various transporters in the placental uptake of ofloxacin in an in vitro model of human villous trophoblasts
Abstract
Hana Polachek,1,* Nir Debotton,2,* Valeria Feinshtein,1 Mazal Rubin,1 Zvi Ben-Zvi,1,‡ Gershon Holcberg,3 Riad Agbaria,1 Arik Dahan1 1Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel; 2Department of Chemical Engineering, Shenkar College of Engineering and Design, Ramat-Gan, Israel; 3Division of Obstetrics and Gynecology, Soroka University Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel *These authors contributed equally to this work ‡Professor Zvi Ben-Zvi passed away on August 4, 2017 Introduction: Six years after the US Food and Drug Administration approval of the broad-spectrum antibiotic ofloxacin (OFLX), the chiral switching of this racemic mixture resulted in a drug composed of the l-optical isomer levofloxacin (LVFX). Since both fluoroquinolones (FQs) were introduced to the pharmaceutical market, they have been widely prescribed by physicians, with careful administration during pregnancy and breastfeeding. Therefore, the role of the influx and efflux placental transporters in the concentrations of these drugs that permeate through human placental barrier model was investigated in this study. Methods: The contribution of major carriers on the transplacental flux of OFLX and LVFX uptake into choriocarcinoma BeWo cells was evaluated in the presence vs absence of well-known inhibitors. Results: Our results reveal that neither the influx transporters such as organic cation transporters, organic anion transporters, and monocarboxylate transporters nor the efflux transporters such as P-glycoprotein or breast cancer resistance protein significantly affected the transport of OFLX. In contrast, multiple transporters revealed pronounced involvement in the transfer of the levorotatory enantiomer in and out of the in vitro placental barrier. These data suggest a non-carrier-mediated mechanism of transport of the racemic mixture, while LVFX is subjected to major influx and efflux passage through the placental brush border membranes. Conclusion: This study provides underlying insights to elucidate the governing factors that influence the flux of these FQs through organ barriers, in view of the controversial safety profile of these drugs in pregnant population. Keywords: drug transport, fluoroquinolones, levofloxacin, ofloxacin, placenta, pregnancy
