Role of the Multidrug Transporter Proteins ABCB1 and ABCC2 in the Diaplacental Transport of Talinolol in the Term Human Placenta

Abstract

ABSTRACT:Placental syncytiotrophoblasts are known to express the efflux transporter proteins P-glycoprotein (ABCB1) and multidrug resistance-associated protein 2 (ABCC2), which are supposed to be a functional part of the human placental barrier. With advancing gestational age, expression of ABCB1 decreases progressively, whereas ABCC2 is more expressed. To evaluate to which extent they contribute to placental barrier function at term, permeability of talinolol, a substrate of both carriers, was measured using a validated human placenta perfusion model. We identified in randomized, crossover experiments a unidirectional transfer of talinolol in the fetomaternal direction because the maternofetal trans- The human placenta brings the maternal and fetal blood circulations closely together, separated only by the single cell layer of the syncytiotrophoblast. It regulates the supply of nutrients and gases, the elimination of fetal waste products, and the exposure to exogenous substances, including drugs. There is growing evidence that energydependent transporter processes are involved in the maternofetal exchange of endogenous and xenobiotic substances. Meanwhile, more than 30 transport proteins were identified that are expressed to the maternal-facing brush-border apical membrane or to the fetal-facing basolateral membrane of the syncytiotrophoblast (Marzolini and Kim, 2005;Evseenko et al., 2006;Myllynen et al., 2007). There is evidence for some of them to be significantly involved in drug disposition, such as the maternal-facing efflux carriers P-glycoprotein (ABCB1) and the multidrug resistance-associated protein 2 (ABCC2), a second member of the ABC transporter family (St. Pierre et al., 2000;Marzolini and Kim, 2005;Ceckova-Novotna et al., 2006;Evseenko et al., 2006). ABCB1 and ABCC2 share a wide overlapping substrate spectrum and may be coregulated, e.g., in the small intestine Jedlitschky et al., 2006). Information on their function in the human placenta, however, is contradictory and limited so far to ABCB1. Because placental ABCB1 expression decreases with advancing gestation age whereas ABCC2 undergoes gestational maturation, we hypothesized that ABCC2 in term placentas may be more important than ABCB1 for the transfer of drugs that are substrates of both carriers (Meyer zu Schwabedissen et al., 2005;Sun et al., 2006). A suitable probe drug to evaluate function of ABCB1 and ABCC2 in humans is the nonmetabolized ␤ 1 -selective blocker talinolol, which is a high affinity substrate of ABCB1 as evidenced by in vitro experiments and pharmacokinetic studies in humans and of ABCC2 as concluded from major changes in disposition in Abcc2-deficient GY/ TR Ϫ rats (Spahn-Langguth et al., 1998;Gramatté and Oertel, 1999;Westphal et al., 2000;Bernsdorf et al., 2003). ␤ 1 -Selective blockers are used in the treatment of hypertension during pregnancy (Magee et al., 2000).We provide evidence from perfusion experiments using the dually perfused human placenta model that the placenta serves as a functional barrier for talinolol a...

Placental ABC Transporters: Biological Impact and Pharmaceutical Significance

“…May et al . reported that the materno-fetal transfer of talinolol in the human placental perfusion model was sensitive to probenecid, consistent with MRP2 involvement in the transplacental transfer of this substrate (164). Bridges et al examined the disposition of the mercuric ions in the placental and fetal tissues.…”

Rapid Modulation of the Organic Anion Transporting Polypeptide 2B1 (OATP2B1, SLCO2B1) Function by Protein Kinase C-mediated Internalization

“…Placenta Perfusion-Immediately after delivery, the fetal and maternal sides of three placentas were perfused as described recently (30). The flow rate was 12 ml/min in the maternal circuit and 4 ml/min in the fetal circuit with an arterial pressure between 25 and 40 mm Hg.…”

“…Internalization of OATP2B1 in a Placenta Perfusion ModelTo answer the question whether PKC-mediated OATP2B1 internalization also plays a role in the biological system, we performed human placenta perfusion studies, a model system that is often used to investigate feto-maternal drug transport and vice versa (30). Using this system we could demonstrate an internalization of OATP2B1 following PMA perfusion (Fig.…”

Placental control of drug delivery

“…In addition to this, it can transport a number of sulfate, glucuronide, and glutathione conjugates [96]. Xenobiotics that are transported by MRP2 include tenofovir disoproxil fumarate and talinolol, among others [48,61,80,97]. …”