Anesth Analg 2002;94:1312-1314
© 2002 International Anesthesia Research Society
OBSTETRIC ANESTHESIA
The Influences of Maternal Albumin Concentrations on the Placental Transfer of Propofol in Human Dually Perfused Cotyledon In Vitro
Yan-Ling He, PhD,
Hiroshi Seno, MD,
Ken Sasaki, MD, and
Chikara Tashiro, MD
Department of Anesthesiology, Hyogo College of Medicine, Nishinomiya City, Japan
Address correspondence and reprint requests to Yan-Ling He, PhD, Department of Anesthesiology, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya City 663-8501, Japan. Address e-mail to Yhe{at}partners.org
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Abstract
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IMPLICATIONS: These results indicate that fetal exposure to propofol can vary considerably depending on maternal plasma albumin concentration. A fractional change in the maternal protein binding of propofol can result in a relatively large difference in fetal exposure.
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Introduction
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Both the physicochemical characteristics of a drug and a variety of physiological factors are important in controlling the placental transfer of a drug. Lipid solubility, degree of ionization, and protein binding of a drug influence the placental transfer. The fetal/maternal ratios of several lipophilic drugs have been demonstrated to be principally determined by protein binding rather than lipid solubility (1,2). Propofol, which has become very popular in anesthetic practice, is a highly lipophilic compound and is extensively bound to plasma protein (3,4). We previously demonstrated that increased albumin concentration in the fetal perfusate significantly facilitated the placental transfer of propofol, and that the protein binding capacity on the fetal side played a dominant role in controlling its placental transfer (5). Both maternal and fetal albumin concentrations show dynamic changes during pregnancy. The maternal albumin concentration varies from 25 to 35 g/L over 12–40 wk of gestation, in addition to the considerable changes of fetal albumin concentrations, with a range of 7.5–39.8 g/L (6). The objective of this study was to further investigate the effects of maternal albumin concentrations on the placental transfer of propofol by using the dually perfused human placental model.
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Methods
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After we obtained approval from our IRB, six placentas from healthy parturients (gestational age, 36–38 wk) undergoing cesarean delivery were collected and transported to the laboratory immediately. Cotyledons with easily recognized maternal and fetal vessels were selected and perfused by using the same method reported previously (5,7). Maternal and fetal circuits were perfused in single-pass mode at the rates of 15 and 2 mL/min, respectively. The perfusate was composed of tissue culture medium 199 modified with Earl’s salts (ICN Biomedicals, Aurora, OH) containing heparin 2500 U/L, gentamycin 50 mg/L, and glucose 1.0 g/L. The perfusate for fetal and maternal circuits was equilibrated with 95% nitrogen/5% oxygen and 95% oxygen/5% CO2, respectively. After a stabilization period of >30 min, propofol (Diprivan; Zeneca Pharmaceuticals, Osaka, Japan) and antipyrine (Wako Pure Chemicals, Osaka, Japan) were added to the maternal perfusate. Human serum albumin (plasma protein fraction; Baxter, Tokyo, Japan) concentrations in the maternal perfusate were varied at 22 and 44 g/L at 60-min intervals while the albumin concentration in fetal perfusate was maintained at 44 g/L. Samples from maternal and fetal veins were collected at 30, 45, and 60 min during each study period. Transplacental clearances (CL) and clearance index (CI) were calculated with the same methods as reported previously (5,7). Briefly, the placental CL was calculated as
equation
where Qf is the flow rate of fetal circulation and Cfv and Cma are the fetal venous concentration and the maternal arterial concentration, respectively. The CI of propofol was calculated by dividing the placental CL of propofol (CLpropofol) by that for antipyrine (CLantipyrine). Human chorionic gonadotropin concentration, glucose consumption, and lactate production were measured to evaluate the viability of the perfused cotyledons. Propofol and antipyrine were mea-sured with high-performance liquid chromatography (5,7). All data are expressed as mean ± SD, and SigmaStat for Windows (Version 1.0; Jandel Scientific, Chicago IL) was used for statistical analysis.
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Results
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The weights of placentas and cotyledons (n = 6) were 535 ± 135 g and 15.5 ± 5.9 g, respectively. Glucose consumption, lactate production, and the pro-duction rate of human chorionic gonadotropin were 0.241 ± 0.046 µmol · min-1 · g-1, 0.324 ± 0.046 µmol · min-1 · g-1, and 5.454 ± 0.586 IU · h-1 · g-1, respectively, characterizing the physiologic integrity and viability of the perfused cotyledons. Propofol concentrations in the maternal artery, maternal vein, and umbilical vein are summarized in Table 1. The umbilical venous concentrations of propofol were significantly reduced when the maternal albumin concentration was varied from 22 to 44 g/L (6.42 ± 1.85 vs 1.88 ± 0.92 µg/mL; P < 0.001). Consequently, a significantly changed fetal/maternal concentration ratio was observed at different maternal albumin concentrations of 22 and 44 g/L (0.51 ± 0.14 vs 0.13 ± 0.06; P < 0.01). Figure 1 illustrates the CLpropofol, the CLantipyrine, and the CIs at different maternal albumin concentrations. Antipyrine serves as an ideal marker of placental transfer because it is of intermediate solubility and does not bind to plasma proteins. The CLantipyrine was not significantly influenced by the maternal albumin concentrations. However, the CLpropofol was decreased to one third when the maternal albumin concentration was varied from 22 to 44 g/L (2.47 ± 0.37 mL · h-1 · g-1 vs 0.72 ± 0.26 mL · h-1 · g-1; P < 0.001). The CIs of propofol were also significantly changed with the maternal albumin concentration (0.80 ± 0.15 vs 0.43 ± 0.13; P < 0.01).
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Table 1. Propofol Concentrations in the Maternal Artery (MA), Maternal Vein (MV), and Umbilical Vein (UV) at Different Maternal Albumin Concentrations
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Figure 1. Transplacental clearances of propofol (CLpropofol) and antipyrine (CLantipyrine) and clearance indexes (CLindex) at maternal albumin concentrations of 22 and 44 g/L.
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Discussion
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The placenta is unique in being perfused on both maternal and fetal surfaces, and fetal blood is separated from that of the mother by the placental trophoblast and the fetal capillary system. The placental extraction ratio of propofol, which was calculated by dividing the maternal arterial concentrations by the differences between maternal arterial and venous concentrations, decreased from 10% to 5% when the maternal albumin concentration was increased from 22 to 44 g/L. This reveals that the decreased placental transfer of propofol can be at least partly attributed to the limited distribution from maternal circulation to placental tissue. The unbound fraction of propofol at a maternal albumin concentration of 22 g/L was 2.6% ± 0.6%, which was two times the unbound fraction at a maternal albumin concentration of 44 g/L (1.3% ± 0.3%). Because only free drugs equilibrate across the placenta, the observed smaller unbound fraction of propofol at a larger albumin concentration can be considered a significant factor that impedes the delivery of propofol from the maternal circuit into the fetal/placental compartment. The dissociation of propofol molecules from albumin may also limit its placental distribution on the maternal side. Placental sequestration and transfer out of the placental tissue into the fetal circulation can also be considered processes that contribute to the decreased placental transfer of propofol. Our previous study demonstrated that the binding capacity when maintaining the fetal albumin concentration at 44 g/L can result in a fetal venous concentration of propofol as large as that in the maternal artery (5). This suggests that transfer out of placental tissue to the fetal circulation would not be considered a rate-limiting process when the maternal albumin concentration is changed. We therefore conclude that the limited distribution from maternal circulation to the placental tissue is the preliminary cause of impeded placental transfer of propofol at a larger maternal albumin concentration.
It is interesting to note that placental transfer of propofol was significantly facilitated by an increased binding capacity in fetal perfusate, whereas maternal protein binding limited the CLpropofol. Fetal exposure to propofol is, therefore, expected to be remarkably variable, depending on the transplacental albumin concentration gradient, because the placental transfer of propofol is dependent on the albumin concentration gradient across the placenta. Furthermore, the umbilical venous concentrations of propofol varied by more than threefold when maternal albumin concentration was changed over a physiologically feasible range during pregnancy (22 to 44 g/L), implying that fetal exposure to propofol may vary considerably depending on the plasma albumin concentration in parturients.
In summary, placental transfer of propofol was significantly impeded by increasing the maternal albumin concentration, indicating that fetal exposure to propofol is expected to vary depending on the plasma albumin concentrations in parturients. A fractional change in the maternal protein binding of propofol, which is a highly protein-bound compound, can result in a relatively large difference in fetal exposure.
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Acknowledgments
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Supported by Grant-in-Aid A-No.10770774 and Grant-in-Aid B-No.11470330 for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan.
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References
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Hamshaw-Thomas A, Rogerson N, Reynolds F. Transfer of bupivacaine, lidocaine and pethidine across the rabbit placenta: influence of maternal protein binding and fetal flow. Placenta 1984; 5: 61–70.[Web of Science][Medline]
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Knott C, Reynolds F. Placental transfer of anticonvulsants in the rabbit: the effect of maternal protein binding and fetal flow. Placenta 1986; 7: 333–8.[Web of Science][Medline]
-
Servin F, Desmonts JM, Haberer JP, et al. Pharmacokinetics and protein binding of propofol in patients with cirrhosis. Anesthesiology 1988; 69: 887–91.[Web of Science][Medline]
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Kirkpartrick T, Cockshott ID, Douglas EJ, et al. Pharmacokinetics of propofol (Diprivan) in elderly patients. Br J Anaesth 1988; 60: 146–50.[Abstract/Free Full Text]
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He YL, Tsujimoto S, Tanimoto M, et al. Effects of protein binding on the placental transfer of propofol in the human dually perfused cotyledon in vitro. Br J Anaesth 2000; 85: 281–6.[Abstract/Free Full Text]
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Krauer B, Dayer P, Anner R. Changes in serum albumin and
 1-acid glycoprotein concentrations during pregnancy: an analysis of fetal-maternal pairs. Br J Obstet Gynaecol 1984; 91: 875–81.[Web of Science][Medline]
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He YL, Tsujimoto S, Seno H, et al. The effects of uterine and umbilical blood flows on the transfer of propofol across the human placenta during in vitro perfusion. Anesth Analg 2001; 93: 151–6.[Abstract/Free Full Text]
Accepted for publication December 20, 2001.
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Abstract
Introduction
