Transplacental Pharmacokinetics of Glyburide, Rhodamine 123, and BODIPY FL Prazosin: Effect of Drug Efflux Transporters and Lipid Solubility

Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University, Prague, Czech Republic.
Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.97). 09/2009; 331(3):1118-25. DOI: 10.1124/jpet.109.160564
Source: PubMed


Breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp) are the most abundantly expressed ATP-binding cassette (ABC) drug transporters in the placenta. They recognize a large, partly overlapping spectrum of chemically unrelated compounds and affect their transplacental passage. In this study we investigate the effect of Bcrp and P-gp on the transplacental pharmacokinetics of their specific and common substrates employing the technique of dually perfused rat placenta. We show that the clearance of rhodamine 123 (P-gp substrate), glyburide (BCRP substrate) and BODIPY FL prazosin (P-gp and BCRP substrate) in fetal-to-maternal direction is 11, 11.2 and 4 times higher, respectively, than that in the maternal-to-fetal direction. In addition, all of these substances were found to be transported from the fetal compartment even against concentration gradient. We thus demonstrate the ability of placental ABC transporters to hinder maternal-to-fetal and accelerate fetal-to-maternal transport in a concentration-dependent manner. However, by means of pharmacokinetic modeling we describe the inverse correlation between lipid solubility of a molecule and its active transport by placental ABC efflux transporters. Therefore, in the case of highly lipophilic substrates, such as BODIPY FL prazosin in this study, the efficacy of efflux transporters to pump the molecule back to the maternal circulation is markedly limited.

Download full-text


Available from: Frantisek Staud, Oct 14, 2015
37 Reads
  • Source
    • "Hoechst 33342 A cell-permeant, bisbenzimide blue-fluorescent dye, nucleic acid stain Scharenberg et al. (2002) Prazosin High-affinity antagonist for the a 1 -adrenergic receptor, fluorescent dye Cygalova et al. (2009), Robey et al. (2001a) Lysotracker Green A green fluorescent dye staining acidic compartments in living cells Litman et al. (2000) Mitoxantrone Antineoplastic agent, topoisomerase II inhibitor, disrupts DNA synthesis and repair Doyle et al. (1998), Litman et al. (2000), Ross et al. (1999) Doxorubicin, daunorubicin, epirubicin Anticancer drugs, anthracyclines interacting with DNA by intercalation and inhibiting DNA biosynthesis, topoisomerase II inhibitors, substrates for BCRP mutated in the position 482 Doyle et al. (1998), Litman et al. (2000) "
    [Show abstract] [Hide abstract]
    ABSTRACT: Abstract The xenobiotic transporters are among the most important constituents of detoxification system in living organisms. Breast cancer resistance protein (BCRP/ABCG2) is one of the major transporters involved in the efflux of xenobiotics. To understand its role in chemotherapeutic and multidrug resistance, it is crucial to establish the determinants of its substrate specificity, which obviously is of high relevance for successful therapy of many diseases. This article summarizes the current knowledge about the substrate preferences of BCRP. We overview the factors which determine its activity, inhibition and substrate recognition, focusing on the structural features of the transporter. BCRP substrate specificity is quite low as it interacts with a spectrum of substances with only a few common features: hydrophobic and aromatic regions, possibly a flat conformation and the metal ion-, oxygen- and nitrogen-containing functionalities, most of which may be the donors/acceptors of H-bonds. Several amino acid residues and structural motifs are responsible for BCRP activity and substrate recognition. Thus, the active form of BCRP, at least a dimer or a larger oligomer is maintained by intramolecular disulfide bridge that involves Cys(603) residues. The GXXXG motif in transmembrane helix 1, Cys residues, Arg(482) and Lys(86) are responsible for maintaining the protein structure, which confers transport activity, and the His(457) or Arg(456) residues are directly involved in substrate binding. Arg(482) does not directly bind substrates, but electrostatically interacts with charged molecules, which initiates the conformational changes that transmit the signal from the transmembrane regions to the ABC domain.
    Drug Metabolism Reviews 07/2014; 46(4):1-16. DOI:10.3109/03602532.2014.942037 · 5.36 Impact Factor
  • Source
    • "In this study, the dually perfused rat term placenta method was employed as described previously [28]. In brief, one uterine horn was excised and submerged in heated Ringer's saline. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In our previous studies we described functional expression of organic cation transporter 3 (OCT3) and multidrug and toxin extrusion 1 (MATE1) protein in the rat placenta. Since metformin is a substrate of both OCT3 and MATE1, in this study we used the model of dually perfused rat placenta to investigate the role of these transporters in metformin passage across the placenta. We observed concentration-dependent transplacental clearance of metformin in both maternal-to-fetal and fetal-to-maternal directions; in addition metformin crossed the placenta from the fetal to maternal compartment even against its concentration gradient. This transport was completely inhibited by MPP(+), a common OCT3 and MATE1 inhibitor. Furthermore, we observed that the oppositely directed H(+)-gradient can drive the secretion of metformin from placenta to maternal circulation, confirming apical efflux of metformin from trophoblast by MATE1. In conclusion, we suggest an important role of OCT3 and MATE1 in the transplacental transfer of metformin.
    Reproductive Toxicology 04/2013; 39. DOI:10.1016/j.reprotox.2013.03.001 · 3.23 Impact Factor
  • Source
    • "In genetically modified mice, Bcrp was shown to limit the fetal exposure to topotecan (Jonker et al., 2000; Jonker et al., 2002), nitrofurantoin (Zhang et al., 2007), phytoestrogen genistein (Enokizono et al., 2007) and glyburide (Zhou et al., 2008). Using dually perfused rat placenta, we have recently observed Bcrp-mediated transport in the feto-maternal direction and proposed that this transporter not only reduces passage of its substrates from mother to fetus but also removes the drug already present in the fetal circulation, even against concentration gradient (Staud et al., 2006; Cygalova et al., 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Pharmacotherapy during pregnancy is often inevitable for medical treatment of the mother, the fetus or both. The knowledge of drug transport across placenta is, therefore, an important topic to bear in mind when deciding treatment in pregnant women. Several drug transporters of the ABC and SLC families have been discovered in the placenta, such as P-glycoprotein, breast cancer resistance protein, or organic anion/cation transporters. It is thus evident that the passage of drugs across the placenta can no longer be predicted simply on the basis of their physical-chemical properties. Functional expression of placental drug transporters in the trophoblast and the possibility of drug-drug interactions must be considered to optimize pharmacotherapy during pregnancy. In this review we summarize current knowledge on the expression and function of ABC and SLC transporters in the trophoblast. Furthermore, we put this data into context with medical conditions that require maternal and/or fetal treatment during pregnancy, such as gestational diabetes, HIV infection, fetal arrhythmias and epilepsy. Proper understanding of the role of placental transporters should be of great interest not only to clinicians but also to pharmaceutical industry for future drug design and development to control the degree of fetal exposure.
    Journal of Drug Targeting 09/2012; 20(9):736-63. DOI:10.3109/1061186X.2012.716847 · 2.74 Impact Factor
Show more