Department of Anaesthesiology, Hyogo College of Medicine, 11 Mukogawa-cho, Nishinomiya City 663-8501, Japan
Accepted for publication: January 31, 2000
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Abstract |
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Br J Anaesth 2000; 84: 2816
Keywords: anaesthetics, propofol; anaesthesia, obstetrics
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Introduction |
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Materials and methods |
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Measurement of propofol binding
The unbound fraction of propofol in the perfusate samples was determined by an ultrafiltration method using the CentrifreeTM Micropartition System (Amicon, Bedford, MA, USA).
Calculations of clearance and clearance index
The placental transfer of propofol and antipyrine was evaluated as transplacental clearance. A single-pass experimental design was used for both maternal and foetal circulations. The transplacental clearance was then calculated as follows:22
where Qf is the flow rate of the foetal circulation, Cfv and Cma are the venous concentration in the foetal circuit and the arterial concentration in the maternal circuit, respectively. Transplacental clearance was estimated at 20 and 30 min in each perfusion period at different albumin concentrations in the foetal perfusate. The clearance index (CI) of propofol was calculated based on the transplacental clearances of propofol (CLpropofol) and antipyrine (CLantipyrine), as follows:
Statistics
All data are expressed as mean (SD). SigmaStat for Windows (Version 1.0; Jandel Scientific, Chicago, IL, USA) was used for the statistical analysis. The propofol concentrations, transplacental clearances and clearance indexes were analysed by one-way repeated measures analysis of variance. If the analysis of variance was found to be significant, Bonferronis test was performed to compare the values at various albumin concentrations in the foetal perfusate with that at 4.4 g litre1. The significance of the difference between placental tissue and maternal venous concentrations of propofol was evaluated with the paired t-test. Differences were considered to be significant when P<0.05.
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Results |
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Discussion |
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Antipyrine serves as an ideal marker of placental transfer because it is of intermediate solubility and does not bind to plasma proteins. The placental clearance of antipyrine remained unchanged throughout the experimental period at different albumin concentrations in the foetal perfusate (Fig. 3), suggesting that the transplacental exchange of small molecules was maintained throughout the perfusion period. The transplacental clearance of propofol increased considerably with increasing albumin concentration, and was significantly greater than that of antipyrine when the albumin concentration in the foetal circulation was 22 g litre1. This result indicates that the placental permeability of propofol might be more efficient than that for antipyrine during the pregnancy period close to term. Increasing the albumin concentration in the foetal perfusate led to a significant increase in the placental transfer rate of propofol, demonstrating that binding to albumin in the foetal circulation is a dominant feature in the control of the placental transfer of propofol. Binding of propofol to plasma was reported to be independent of the substrate concentration over the range 0.04150 mg ml1;32 therefore, the binding capacity for propofol is expected to be proportional to the albumin concentration according to the formula B/F = nKaP, where B is the bound drug concentration, F is the unbound drug concentration, n is the number of binding sites per molecule of protein, Ka is the affinity constant and P is the concentration of binding protein.33 Consistent with this suggestion, the observed unbound fractions of propofol in foetal venous samples were 16.9 (SD 3.6), 12.7 (3.3), 6.8 (1.5), 4.2 (1.1) and 2.8 (0.5)% at albumin concentrations of 4.4, 11, 22, 33 and 44 g litre1, respectively. Therefore, the facilitated placental transfer of propofol can be readily explained by the differences in protein-binding capacity at various albumin concentrations, because the increased protein-binding capacity for propofol at higher albumin concentrations in the foetal perfusate allows a larger amount of the drug to cross the placenta faster. This is consistent with observations using the same perfused human placenta model with several other lipophilic drugs, including thiopental, demonstrating that transplacental distribution was markedly influenced by maternal and foetal protein capacity.17 20 3437
The placenta is unique in being perfused on both its maternal and its foetal surface, and foetal blood is separated from that of the mother by the placental trophoblast and the foetal capillary system. Therefore, the transplacental exchange of a drug comprises three processes: distribution from the maternal circulation to the placenta; placental sequestration, including intracellular binding to placental component(s) and placental metabolism; and transfer out of the placenta to the foetal and maternal circulations. The maternal venous concentrations were not influenced by the albumin concentration in the foetal perfusate, resulting in constant extraction of propofol from the maternal circulation, which was about 15% (Fig. 2). Therefore the considerable facilitation of the transplacental exchange of propofol by increased albumin concentrations can be attributed to the facilitated placental sequestration of propofol from the placenta to the foetal circulation. That is, the placental transfer of propofol is restricted by placental retention at lower albumin concentrations in the foetal perfusate. Consistent with this, high placental tissue concentrations of propofol (53.3 (20) µg ml1) were observed at the end of the experiment. This implies that the placenta plays an important role in protecting the foetus from exposure to propofol administered to the mother as a depot. On the basis of a simple model that has been proposed to interpret the effects of binding to serum albumin and to the placenta on the placental transfer of a drug,35 the protein-binding capacity and the relative affinity of propofol for maternal and foetal plasma proteins and to placental component(s) can be considered to be the predominant features of the control of transfer across the placenta. Furthermore, restricted foetal transfer associated with pronounced placental accumulation for lipophilic drugs, such as bupivacaine, dexmedetomidine and sufentanil, has also been reported.17 18 20 21
The foetal/maternal concentration ratio of propofol varied with the albumin concentration in the foetal perfusate, ranging from 0.74 (0.28) to 1.13 (0.15) over the albumin concentration range of 2244 g litre1 in this human perfused cotyledon model. This indicates that the clinically measured foetal/maternal ratio, which is considered to be an index of the placental transfer of a drug, can show a wide range depending on the plasma protein concentrations. It is of note that the free concentrations of propofol in the foetal perfusate did not change significantly, irrespective of the considerably increased total propofol concentrations (Fig. 2). Therefore, the pharmacological effects of propofol will not be influenced by the plasma albumin concentration in the foetus. However, in vivo, foetal uptake of propofol is a dynamic process, and on the basis of the lower umbilical arterial concentrations compared with those in umbilical vein samples it has been suggested that the neonate continues to take up propofol during delivery, a process that may involve neonatal metabolism.9 Protein binding can be seen as a mechanism whereby propofol is transported to and from the peripheral tissues; therefore, the storage function of plasma protein binding should not be neglected. The enormously increased bound component in the foetus at higher albumin concentrations might result in a prolonged effect of propofol on the foetus, and more importantly, on the neonate after birth.
In summary, placental transfer of propofol was significantly facilitated by increased albumin concentrations in the foetal circulation, indicating that the binding capacity to albumin in the foetal circulation is a dominant feature in the control of the transplacental exchange. The high propofol concentration in placental tissue demonstrates that the placenta plays an important role in protecting the foetus from exposure to propofol administered to the mother as a depot. The free concentration of propofol did not change significantly despite the considerably increase in total propofol concentration in the foetal circulation associated with the increased albumin concentration, suggesting that the pharmacological effect of propofol on the foetus can be expected to be fairly constant and predictable from the maternal propofol concentration. However, the storage function of plasma protein binding should not be neglected.
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Acknowledgements |
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Footnotes |
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References |
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