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

Departments of Clinical Pharmacology (K.M., V.M., W.S.), Pharmacology (H.K.K.), Gynecology and Obstetrics (M.Z.), and Neonatology and Pediatric Intensive Care (K.L., C.F.), University of Greifswald, Greifswald, Germany

(Received October 25, 2007; Accepted January 10, 2008)

	Abstract

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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 transfer was significantly lower (0.663 ± 0.188 versus 0.394 ± 0.067 relative to creatinine permeability, p = 0.012). Maternofetal permeability was increased by the ABCC2 inhibitor probenecid (0.59 ± 0.15 versus 0.68 ± 0.13, p = 0.028) and the nonspecific inhibitor verapamil (0.53 ± 0.09 versus 0.66 ± 0.16, p = 0.028) but was not influenced by the ABCB1 inhibitor valspodar (PSC833) (0.48 ± 0.11 versus 0.46 ± 0.09, p = 0.345). Genetic polymorphisms of ABCB1 and ABCC2 lacked significant influence on expression of the carriers and permeability of talinolol, respectively. In conclusion, maternofetal transfer of talinolol is restricted by a unidirectional process that is influenced by inhibitors of ABCC2.

We provide evidence from perfusion experiments using the dually perfused human placenta model that the placenta serves as a functional barrier for talinolol as caused by a maternal-directed efflux transport. Furthermore, we evaluated the influence of the most common ABCB1 and ABCC2 polymorphisms and of the inhibitors PSC833 (for ABCB1), probenecid (for ABCC2), and verapamil (nonspecific) on the maternofetal transfer of the probe drug (Horikawa et al., 2002; Modok et al., 2006). Our data were obtained in quality-controlled perfusion experiments using human term placentas of carefully selected healthy women.

	Materials and Methods

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Subjects. To evaluate the influence of genetic and drug-induced variability in function of ABCB1 and ABCC2 on the placental transfer of the probe drug talinolol, we used the human placenta perfusion model as initially described by Schneider et al. (1972). Seventy-five human placentas from healthy parturient women after noncomplicated vaginal or cesarean delivery and written informed consent were prepared for perfusion. Per protocol, analysis was possible with 26 of them (gestation 38–41 weeks, placenta weight 416–996 g, newborn body weight 2920–4470 g, Apgar score 7–10). The ABCB1 and ABCC2 genotypes were as follows: ABCB1 2677G>T/A, 8 GG, 8 GT, 8 TT, 2 GT/A; ABCB1 3435C>T, 6 CC, 14 CT, 6 TT; ABCC2 –24C>T, 22 CC, 4 CT, 1249G>A, 15 GG, 7 GA, 4 AA; and 3972C>T, 16 CC, 6 CT, 4 TT. The study was approved by the local ethical committee.

Placenta Model. Immediately after delivery, the fetal and maternal sides of the placenta were perfused as described recently (Bachmaier et al., 2007). The flow rate was 12 ml/min in the maternal circuit and 4 ml/min in the fetal circuit, resembling physiological flow rates. The fetal arterial pressure was maintained between 25 and 40 mm Hg, and the total perfusion volume in each circuit was 140 ml. At the beginning of all the experiments, the placenta was open loop–perfused for 30 min for removal of blood, followed by close-loop perfusion for 60 min for stabilization and detection of leakage or noncongruent maternal and fetal perfusion. There was no loss of perfusate from the fetal into the maternal compartment at the beginning of the experiments. Experiments were excluded if fetal perfusion pressure was >50 mm Hg, loss of perfusate >4 ml/h, and in cases of noncongruence between the perfusion compartments. Tissue samples were dissected from peripheral cotyledons before perfusion for genotyping and from the perfused cotyledon after perfusion for mRNA and protein quantification.

Study Protocols. The experiments were performed randomized, controlled, two-period, crossover with 30-min washout perfusion. In the first study using eight placentas, permeability of talinolol in the fetomaternal and maternofetal directions was compared. After the stabilization period, talinolol (0.8 µM, AWD Pharma, Dresden, Germany), antipyrine (0.4 mM, Sigma, Steinheim, Germany), and creatinine (1.3 mM, Arcos Organics, Geel, Belgium) were added randomly either to the maternal or fetal circuit (final concentrations). Samples (2 ml) were taken from both circuits after 5, 10, 15, 20, 30, 45, 60, 90, 120, and 150 min after administration and substituted by perfusion medium.

In our second experiment, the maternofetal permeability of talinolol, antipyrine, and creatinine was measured without and in the presence of verapamil (30 µM; Sigma), PSC833 (1.8 µM; Novartis, Basel, Switzerland), or probenecid (10 mM; Sigma) using six placentas in each case. All the inhibitors were added to the perfusion medium of the maternal and fetal circulation in concentrations that have been shown in former studies to modulate the efflux carriers (Pauli-Magnus et al., 2000; Naruhashi et al., 2002; Mölsä et al., 2005).

Genotyping, mRNA Expression, and Protein Content of ABCB1 and ABCC2. The ABCB1 polymorphisms 2677G>T/A and 3435C>T and ABCC2 –24C>T, 1249G>A, and 3972C>T were screened by polymerase chain reaction/restriction fragment length analysis. ABCB1 and ABCC2 mRNA expression was quantified by real-time reverse transcription-polymerase chain reaction analysis (Giessmann et al., 2004). Placental protein levels of ABCB1 and ABCC2 were measured by Western blot analysis using for ABCB1 the monoclonal C219 (1:1000) and for ABCC2 the M₂III-6 (1:500) antibodies (Alexis Biochemicals, Grünberg, Germany).

Assays for Glucose, Lactate, Creatinine, Talinolol, and Antipyrine. Glucose and lactate concentrations were measured amperometrically using the Super GL Ambulance (Ruhrtal Labor Technik, Möhensee, Germany), and creatinine was measured using the kit Dimension CREA (Dade Behring, Marburg, Germany).

Talinolol was quantified with a high-performance liquid chromatography (HPLC) method as described recently for human serum (Westphal et al., 2000). The method was validated between 0.005 and 1.0 µg/ml perfusion medium. Within-day accuracy of the method was between –2.8 and 8.3% of the nominal concentrations and precision 2.2 to 6.5% of means. The following between-day variability was assessed with quality control samples containing 0.025, 0.25, and 0.75 µg/ml talinolol: accuracy –2.9 to 4.1%, precision 4.3 to 10.6% of the nominal and mean values, respectively.

Antipyrine in concentrations between 0.5 and 50 µg/ml was assayed by isocratic HPLC. In brief, 100 µl of perfusion medium was mixed with 400 µl of distilled water, 100 µl of 4 N sodium hydroxide, and 100 µl of internal standard solution (0.027 mg/ml phenacetin) and extracted twice with 3 ml of diethyl ether. After evaporation to dryness, the residue was dissolved in 140 µl of the mobile phase (triethylammonium phosphate buffer, pH 3.0, mixed with 35% methanol). Fifty microliters was injected into the HPLC (Merck-Hitachi, Düsseldorf, Germany) equipped with the column Merck LiChroCart 125-4 HPLC cartridge filled with LiChrospher 100 RP 18e (temperature 30°C, flow 1 ml/min). The following quality parameters were obtained: within-day accuracy and precision –7.8 to 9.5% and 2.8 to 11.2%, respectively; between-day accuracy –0.4 to 2.0% and precision 5.2 to 11.4% of the nominal and mean values, respectively.

Biometrical Evaluation. Permeability (P) of talinolol, creatinine, and antipyrine was calculated according to the equation P = C_fet/(weight_cot x [AUC_mat – AUC_fet]) with C_fet to be the concentration in the fetal circuit at the end of perfusion, AUC_mat the area under the concentration-time curve (AUC) in the maternal circuit, AUC_fet the AUC in the fetal circuit, and weight_cot the wet weight of the cotyledon (Bajoria and Fisk, 1998). Ratios of the talinolol permeability over the creatinine permeability were calculated to normalize for individual differences caused by paracellular transfer (Brownbill et al., 2000). Means ± S.D. or medians, minimums, and maximums are given. Sample statistics were done using the Wilcoxon and Mann-Whitney tests and Spearman rank correlation as appropriate.

	Results

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Method Validation. Placental carbohydrate metabolism remained unchanged during the time of perfusion and was also not influenced by talinolol, PSC833, verapamil, or probenecid as confirmed by monitoring glucose consumption and lactate production. Furthermore, the passive placental transport was also not significantly influenced by the experimental conditions as verified by the permeability data for creatinine, a surrogate for paracellular transfer, and for antipyrine, a measure for nonionic simple diffusion (Table 1) (Schneider et al., 1972; Brownbill et al., 2000). Because of the lower perfusion rate in the fetal circulation, antipyrine permeability in the maternal direction was expectedly lower than in the fetal direction (p = 0.069). Therefore, permeability of talinolol in the maternal direction might have been underestimated.

Unidirectional Transfer of Talinolol. We identified a significant unidirectional placental transfer of talinolol in the fetomaternal direction. The permeability of talinolol from the maternal to the fetal circulation was significantly lower than that from the fetal to the maternal side of the placenta (0.006 ± 0.002 ml x min^–1 x g^–1 versus 0.013 ± 0.007 ml x min^–1 x g^–1, p = 0.012). Similarly significant differences in permeability were obtained after considering the differences in paracellular transfer by normalization of the data to creatinine permeability (0.39 ± 0.07 versus 0.66 ± 0.19, p = 0.012) (Fig. 1).

View larger version (20K): [in this window] [in a new window]   FIG. 1. Permeability of talinolol normalized to creatinine permeability in the maternofetal versus fetomaternal direction (n = 8). Wilcoxon signed rank test was used to evaluate differences.

View larger version (18K): [in this window] [in a new window]   FIG. 2. Permeability of talinolol normalized to creatinine permeability in maternofetal direction in the presence of PSC833, probenecid, and verapamil (n = 6). Wilcoxon signed rank test was used to evaluate differences.

	Discussion

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We provided valid experimental data on unidirectional placental transfer of talinolol using dually perfused human placentas that were obtained from carefully selected healthy women. The metabolic conditions during the perfusion for 7 h were stable as oxygen consumption and lactate production have not changed. Nevertheless, we used randomized, controlled, crossover designs to minimize study-related intrasubject differences such as time-dependent changes in expression of the transporters. Furthermore, we corrected our data with talinolol to the permeability of creatinine to minimize influence of paracellular transfer (Brownbill et al., 2000). In all our maternofetal transfer studies, there were also no significant differences in antipyrine permeability, which is an accepted surrogate to characterize placental passive diffusion (Schneider et al., 1985). As expected because of the lower perfusion rate in the fetal circulation, antipyrine permeability in the maternal direction was somewhat lower even though not statistically different. Therefore, permeability of talinolol in the maternal direction may have been underestimated if perfusion is also rate-limiting for the transfer of talinolol.

In our inhibition experiments, only the maternofetal transfer was measured using a crossover design because this is the clinically relevant transport route. However, it is recommended for future studies to evaluate whether inhibition of efflux carriers in the syncytiotrophoblast leads to decrease of the fetomaternal permeability.

It is largely accepted that endogenous and xenobiotic compounds are exchanged via the human placenta by active transporters localized to the basal and apical membrane of the syncytiotrophoblast such as the efflux pumps ABCB1, ABCC1 (MRP1), ABCC2, and ABCG2 (BCRP) or certain members of the organic anion transport polypeptides (OATP1A2, OATP2B1), the organic cation transporters (OCT3, OCTN1, OCTN2), or the organic anion transporters (OAT1, OAT3) (Marzolini and Kim, 2005; Evseenko et al., 2006). Their function in the human placenta, particularly the interplay between uptake and efflux carriers to initiate unidirectional substance transfer, however, is so far nearly unknown. The only exception is ABCB1, which was shown to be involved in the maternal directed efflux of saquinavir, methadone, paclitaxel, and quetiapine (Mölsä et al., 2005; Nanovskaya et al., 2005; Rahi et al., 2007). Therefore, ABCB1-mediated efflux seems to be the mechanism behind that what is called "placenta barrier" for many drugs that reach much lower blood concentrations in the fetus than in the mother despite low plasma protein binding, e.g., digoxin, calcium channel blockers, β-receptor blockers, antidepressants, and antiretroviral drugs (Marzolini and Kim, 2005; Evseenko et al., 2006).

We provide for the first time evidence that the multidrug transporter ABCC2 may be also a functional part of the "placenta barrier." In late pregnancy, ABCC2 may be more important than ABCB1 because it is increasingly expressed with advancing pregnancy, which is contrary to ABCB1, for which a progressive 2-fold decrease in expression was observed between the early pregnancy and term (Meyer zu Schwabedissen et al., 2005; Sun et al., 2006). This hypothesis is confirmed by our data with talinolol, which is a substrate of ABCB1 and ABCC2 (Spahn-Langguth et al., 1998; Bernsdorf et al., 2003). Placental transfer of talinolol at term was in our study more influenced by ABCC2 than ABCB1 as concluded from its higher permeability in the fetal direction in the presence of the ABCC2 inhibitor probenecid but not in the presence of the ABCB1 inhibitor PSC833 (Horikawa et al., 2002; Modok et al., 2006).

Obviously, ABCC2 dominates drug efflux in late pregnancy to a higher extent than ABCB1. This is supported by observations with digoxin, which is a substrate of ABCB1 but not of ABCC2 (Lowes et al., 2003). Therefore, the transplacental transfer of digoxin at term was not influenced by the ABCB1 inhibitors verapamil and quinidine in the dually perfused placenta model (Holcberg et al., 2003). One may speculate that ABCC2 contributes also to placental barrier functions for saquinavir and paclitaxel, which are substrates of ABCB1 and ABCC2. For both drugs it was already shown by competition experiments with specific ABCB1 inhibitors that at least ABCB1 is involved (Janneh et al., 2005; Mölsä et al., 2005; Nanovskaya et al., 2005; Lagas et al., 2006).

However, the unidirectional placental transfer of drugs seems to be an extremely complex process as also evidenced by our results. In the presence of the widely used ABCB1 inhibitor verapamil, the maternofetal talinolol permeability was significantly increased, even to a higher extent than in the presence of probenecid, although the specific modulator PSC833 lacked marked influence (Naito and Tsuruo, 1989). R-Verapamil is also known to modulate ABCC1 and OATP as confirmed for the uptake of fexofenadine (Cvetkovic et al., 1999; Perrotton et al., 2007). ABCC1 seems to be localized to the basal and brush-border membrane of the syncytiotrophoblast and to the blood vessel endothelia, and it undergoes gestational maturation. The OATP transporters OATP2B1 and OATP1B3 are localized to the basal membrane of the syncytium and are obviously involved in uptake of steroid sulfates and unconjugated bilirubin (Evseenko et al., 2006). Functional interaction of basolateral uptake transporters (e.g., OATP2B1, OATP1B3) with apical efflux carriers (e.g., ABCB1, ABCC2, ABCG2) may be the way steroids, bilirubin, and drugs pass the placenta in the fetomaternal direction. This conception is in line with the recent observation that the expression of OATP2B1 and ABCG2 in the human placenta is significantly correlated (Grube et al., 2007). There is evidence that OATPs are involved in disposition of talinolol (Schwarz et al., 2005). Therefore, verapamil may have increased placental talinolol permeability by inhibition of basolateral OATPs. Whether inhibition of ABCC1 by verapamil is also involved in modulation of placental talinolol transfer needs further investigation. In this context it should be mentioned that probenecid is also an inhibitor of ABCC1 in vitro, which might have contributed to facilitated talinolol permeability in the fetal direction (de Jong et al., 2003). In our study it was not evaluated whether the highly abundant ABCG2 is also involved in diaplacental transfer of talinolol as shown for glyburide using placenta membrane vesicles and the ABCG2 inhibitor novobiocin (Kraemer et al., 2006; Gedeon et al., 2008). Furthermore, ABCC1, ABCB1, ABCC2, and ABCG2 have a wide spectrum of substrate in common. In future mechanistic studies, more specific and potent inhibitors would be required to clearly show the function of placental drug transport proteins.

There is evidence from literature that the genetic polymorphisms ABCB1 G2677T and C3435T and ABCC2 G1249A are associated with altered expression of the transporters in the human placenta (Hitzl et al., 2004; Meyer zu Schwabedissen et al., 2005). The statistical power in our study, however, was too low to confirm functional relevance of this genetic variability for placental talinolol transfer because of the low sample size (n = 26) and the high intersubject variability of the permeability (35%).

	Conclusion

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The maternofetal transfer of talinolol is restricted by a unidirectional process that is influenced by inhibitors of ABCC2. There is evidence that additional active transporters are involved. However, the efflux of talinolol seems to be low and obviously not of clinical relevance.

	Acknowledgments

 
We thank Gitta Schumacher, Edita Kaliwe, and Danilo Wegner for excellent technical assistance.

	Footnotes

 
The authors have no conflicts of interest. The data were presented in a poster during the 8th Annual Congress of the Association of Clinical Pharmacology in Würzburg, Germany by Minarikova et al., Abstract in Int J Clin Pharmacol Ther 44/10, 2006, and in an oral presentation during the Annual Meeting of the ASCPT in Anaheim, California by Minarikova et al., Abstract in Clin Pharmacol Ther 81 (Suppl 1), OI-C-I, 2007.

Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

doi:10.1124/dmd.107.019448.

ABBREVIATIONS: ABCB1, P-glycoprotein; ABCC2, multidrug resistance-related protein 2; PSC833, valspodar; HPLC, high-performance liquid chromatography; AUC, area under the concentration-time curve; OATP, organic anion transport polypeptide.

Address correspondence to: Werner Siegmund, Department of Clinical Pharmacology, Ernst Moritz Arndt University, Friedrich-Loeffler-Str. 23d, D-17487 Greifswald, Germany. E-mail: siegmuw{at}uni-greifswald.de

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This Article Abstract Full Text (PDF) All Versions of this Article: dmd.107.019448v1 36/4/740    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by May, K. Articles by Siegmund, W. Search for Related Content PubMed PubMed Citation Articles by May, K. Articles by Siegmund, W.