The role of various transporters in the placental uptake of ofloxacin in an in vitro model of human villous trophoblasts

Abstract

IntroductionSix 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.MethodsThe 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.ResultsOur 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.ConclusionThis 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.

Applicability of free drug hypothesis to drugs with good membrane permeability that are not efflux transporter substrates: A microdialysis study in rats

“…In an in vitro study, neither P‐gp nor BCRP affected the efflux transport of ofloxacin. In contrast, it revealed pronounced MRPs involvement in the transfer of ofloxacin 44 . The ER values of ganciclovir were less than 2.0 in MDR1‐MDCK assay, and equal to 2.61 in Caco‐2 assay (Tables 3 and 4).…”

The Effects of P‐glycoprotein Modulators on the Transition of Levofloxacin to Rat Brain, Testicle, and Plasma: In Vivo and In Silico Studies

“…It has been demonstrated that LVX is an OATP substrate, [87] and DEX induces this influx of protein [82] . Furthermore, LVX is both uptake and excreted along the placental brush border membranes; [88] and since LVX carries a mono carboxyl group, the mono carboxyl transporter (an OATP member) plays a role in its passage to the tissues [89] . Considering that DEX is a substrate of P‐gp [90] and there is a competition between the two substrates for binding to P‐gp [89] , high doses of DEX may have reduced LVX binding to P‐gp because the in silico results of our study showed that DEX and LVX could interact in similar regions of the binding points.…”

Maternal–Fetal Exposure to Antibiotics: Levels, Mother-to-Child Transmission, and Potential Health Risks

“…123 The important pathways are passive diffusion and active transport, controlling the transport of xenobiotics on the endothelial wall of maternal capillaries and from maternal to fetal blood circulation. 124 In most cases, passive diffusion from high to low concentration areas is the most dominant pathway of the transplacental transport of antibiotics. Passive diffusion does not require energy, and low molecular weight, nonionized, and lipid-soluble essentially exhibit unimpeded diffusion.…”

“…Transplacental transfer of antibiotics depends primarily on common mechanisms governing transfer of molecules across biological membranes, namely passive diffusion, active transport, facilitated diffusion, transcellular diffusion between adjacent cells, and pinocytosis . The important pathways are passive diffusion and active transport, controlling the transport of xenobiotics on the endothelial wall of maternal capillaries and from maternal to fetal blood circulation . In most cases, passive diffusion from high to low concentration areas is the most dominant pathway of the transplacental transport of antibiotics.…”