Maternal–fetal transfer of indocyanine green across the perfused human placenta
Graphical abstract
Maternal to fetal ICG transfer is decreased by organic anion transporting polypeptides (OATPs) inhibitor rifampin.
Introduction
Indocyanine green (ICG) is the only US Food and Drug Administration approved near infrared (NIR) fluorophore. It is administered intravenously at doses of up to 25 mg in adults [1]. In pregnant women, ICG has been used for estimation of hepatic function [2], [3] and for measurement of cardiac output during pregnancy [4], labor [5] and cesarean delivery [6]. Over past years, ICG has been mostly used for ophthalmic angiography. In a survey among vitreoretinal-trained physicians regarding the use of ICG angiography during pregnancy, 83% had seen at least 1 pregnant woman who required ICG angiography or fluorescein angiography. Twenty four percent withheld ICG angiography, largely because of fear of teratogenicity or lawsuit [7].
After administration, ICG binds tightly to plasma proteins. It has a half-life of several min in blood, which allows repeated intraoperative i.v. administration for fluorescence angiography. ICG is excreted unchanged by the liver [8], following uptake into hepatocytes by the organic anion transporting polypeptide (OATP)1B3 and the human Na+-taurocholate co-transporting polypeptide (NTCP) [9]. Excretion into the bile is mediated by the multidrug resistance proteins MDR3 and MRP2 [10]. Recently, P-glycoprotein (P-gp) has also been shown by us to contribute to ICG's efflux from cells [11]. Because ICG is a large, charged and highly plasma protein bound molecule, its extravascular distribution is limited. Thus, ICG's transfer through membranes largely depends on transporters [12].
Previous studies in humans demonstrated that ICG is not detectable in fetal cord blood or in umbilical vein blood collected immediately after birth [2], [4], [5], [6], [7], [13]. However, it is difficult to accurately determine the transplacental kinetics of a particular compound by sampling maternal and cord blood at term [14]. Samples are obtained at only one time point, which is often variable among study subjects, and maternal and fetal sample collection times may not be the same. Indeed, we have recently shown that ICG is detectable in mice fetuses and that medications can significantly enhance ICG distribution into the fetus [15]. Hence, the purpose of the current study was to evaluate the maternal-to-fetal transfer of ICG using the ex vivo placental perfusion model and the effects of transporter inhibitors on these processes. We used two transporter inhibitors, the non-selective OATP inhibitor rifampin (an established inhibitor of OATPs 1A2, 1B1, 1B3, and 2B1) and valspodar, a P-gp inhibitor [16]. OATP4A1 and OATP2B1 have been localized to the apical and the basolateral membranes of placental syncytiotrophoblasts, respectively, where they mediate placental substrate uptake. P-gp is a major efflux transporter at the apical syncytiotrophoblasts membrane [16]. Our study represents a step towards improved understanding of the mechanisms mediating ICG's transplacental transfer. This information may be helpful for predicting potential alteration in fetal ICG exposure due to interactions with medications.
Section snippets
The placentas
The study was approved by the Wolfson Medical Center IRB Local Committee (Protocol # #0040-10-WOMC). Written informed consent was obtained from participants prior to delivery. Placentas from healthy uncomplicated pregnancies were collected immediately after elective cesarean deliveries. Prior to perfusion, placentas were carefully inspected and those with visible tears were discarded.
Perfusion of placental cotyledons
The placental perfusion system contained two independent maternal and fetal perfusion circuits that individually
Patient characteristics
The clinical characteristics of the pregnancies for placentas studied are presented in Table 1, which is a slight modification of the recommended format for clinical data presentation [22]. There was no statistically significant difference between the control and rifampin-treated placentas in terms of maternal age (p = 0.42), week of gestation (p = 0.14) and the weight of the perfused cotyledon (p = 0.42). The parameters of the valspodar-treated placenta were within the range of the control group.
Placental viability
The
Conclusions
The transfer of ICG to cord blood has been shown in humans to be very low [2], [4], [5], [6], [7], [13], attributed to high binding to plasma proteins [8], [23], [24], [25] and limited diffusion. Our findings, using the dually-perfused human placenta, agree with a very low fetal:maternal ICG ratio. ICG's low transfer across the placenta is unlikely to be the result of placental metabolism because this compound is not known to be metabolized in humans [8]. ICG's high molecular weight and
Transparency document
Acknowledgements
The authors acknowledge the support of the European Commission FP7-PEOPLE-2011-CIG grant 293800 and the Israel Science Foundation (ISF) Grant 506/13. This work is part of the Ph.D. thesis of Ms. Miriam Rubinchik-Stern.
Sara Eyal is affiliated with the David R. Bloom Centre for Pharmacy and Dr. Adolf and Klara Brettler Centre for Research in Molecular Pharmacology and Therapeutics at The Hebrew University of Jerusalem, Israel.
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