title: Near Infrared Imaging of Indocyanine Green Distribution in Pregnant Mice and Effects of Concomitant Medications.
abstract: The transfer of indocyanine green (ICG) across the placenta is considered to be very low based on measurements in fetal blood. The goal of this study was to evaluate in mice ICG's distribution within fetuses themselves and effects of concomitant medications on fetal exposure. Mid-gestational (day 12.5) and late-gestational (day 17.5) age mice were imaged after administration of ICG (0.167 mg), in the presence and the absence of the organic anion transporting polypeptide (OATP) inhibitor rifampin (10 mg/kg, n = 11, or 20 mg/kg, n = 1) or the P-glycoprotein inhibitor valspodar (12.5 mg/kg). In vivo ICG emission intensity was followed by ex vivo analysis of blood and tissue emission. Both valspodar and rifampin increased ICG's emission intensity within maternal tissues. In addition, valspodar enhanced the ex vivo signal in mid-pregnancy placentae (2.1-fold; p < 0.01) and fetuses (2.4-fold; p < 0.01), and reduced late-pregnancy placenta:blood and fetus:blood ratios. Rifampin increased placental (1.4-fold, p < 0.05, and 2.3-fold, p < 0.01, in mid- and late-pregnancy, respectively) and fetal (2.2-fold, p < 0.01, and 3.2-fold, p < 0.01, in mid- and late-pregnancy) ICG signal. Similarly to valspodar, late-pregnancy placenta:blood and fetus:blood ratios were reduced by rifampin. Both inhibitors enhanced ICG's emission in fetal leg, liver, and brain. In conclusion, ICG distribution into the mouse fetus can be enhanced when used concomitantly with OATP or P-glycoprotein inhibitors. The greater distribution within individual fetal tissues is likely related to ICG's greater transplacental transfer. Until further data are available on ICG's safety when combined with medications that affect its maternal handling, such combinations should be used with caution.
authors.affiliation: Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem , Jerusalem, Israel.
authors.forename: Ameer
authors.initials: A
authors.lastname: Bishara
authors.affiliation: Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem , Jerusalem, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Meir
authors.affiliation: Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem , Jerusalem, Israel.
authors.forename: Emma
authors.initials: E
authors.lastname: Portnoy
authors.affiliation: Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem , Jerusalem, Israel.
authors.forename: Miri
authors.initials: M
authors.lastname: Shmuel
authors.affiliation: Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem , Jerusalem, Israel.
authors.forename: Sara
authors.initials: S
authors.lastname: Eyal
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000818:Animals; D000904:Antibiotics, Antitubercular / Q000494:pharmacology; D004396:Coloring Agents / Q000737:chemistry / Q000493:pharmacokinetics; D003524:Cyclosporins / Q000494:pharmacology*; D003952:Diagnostic Imaging; D005260:Female; D007208:Indocyanine Green / Q000737:chemistry* / Q000493:pharmacokinetics*; D051379:Mice; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors; D010920:Placenta / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy; D012293:Rifampin / Q000494:pharmacology*; D019265:Spectroscopy, Near-Infrared / Q000379:methods*; D014018:Tissue Distribution
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000904:Antibiotics, Antitubercular; D004396:Coloring Agents; D003524:Cyclosporins; D027361:Organic Anion Transporters; D007208:Indocyanine Green; C070272:valspodar; D012293:Rifampin
keywords: P-glycoprotein; indocyanine green; molecular imaging; near-infrared imaging; organic anion transporting polypeptides; placenta; pregnancy