For injected drugs, it is typically assumed that only a fraction of the circulating drug (e.g., the free drug concentration) is able to cross natural protective biological membranes, such as the blood-brain barrier and the heart’s endothelial barrier.^1,2 As such, research on a drug’s binding properties is of great importance when evaluating the optimal drug dose and overall safety profile. This article will discuss the binding of propofol in the blood.

Propofol is one of the most commonly administered intravenous anesthetic agents. Its rapid and smooth induction, lack of excitation phenomena, rapid terminal half-life, and low incidence of postoperative nausea and vomiting contribute to the drug’s favorable pharmacological profile.³ Despite its frequent use in clinical settings, research on the binding properties of propofol remains scarce. 

Researchers from a French university collected blood samples from healthy males aged 28-47 with type A+ blood and separated the blood components to isolate erythrocytes. Serum was obtained from the patients by allowing their blood samples to clot before removing the liquid component.⁴ Researchers also obtained human serum albumin, human α₁-acid glycoprotein, human high-density lipoproteins, and human low-density lipoproteins.² Propofol was added to aliquots of erythrocytes, human serum, and serum protein concentrations, and then incubated. At clinically relevant concentrations, propofol free fraction ranged from 1.2% at an anesthetic dose of 2.8 μm to 1.7% at a dose of 89.9 μm. 50% of the administered propofol was bound to erythrocytes; of that 50%, about a third was bound to erythrocyte cell membranes and the remaining two-thirds was bound to intracellular components. Another 48% was bound to serum proteins. The study concludes about 98% of propofol binds to blood components, with red blood cells and serum proteins being equally binding.

Given this percentage, the propofol free fraction would likely only be affected if there were major changes in blood composition, which are caused by stress, inflammation, infectious agents, or the toxic effects of endogenous, environmental, and pharmacological compounds.⁵ On the other hand, isolated anemia without any significant change in serum proteins would have little effect on the propofol free fraction, since the lack of erythrocytes would be replaced by proteins. A significant decrease in serum proteins may have a larger effect, since a decrease in albumin content decreases the binding capacity of serum, which in turn increases the free fraction. For example, a 20% decrease in binding capacity may induce a 12% increase in free fraction, and a 50% decrease may induce a 40% increase in free fraction.² Therefore, anesthesiologists should carefully monitor the propofol free fraction, taking care that it does not exceed .5 μm. If the patient also suffers from hypoalbuminemia, greater precautions should be taken, and a lower anesthetic dose may be recommended.²

References

1. Tozer, Thomas N. “Concepts Basic to Pharmacokinetics.” Pharmacology & Therapeutics, vol. 12, no. 1, Jan. 1981, pp. 109–31. https://doi.org/10.1016/0163-7258(81)90077-2 
2. Mazoit, Jean Xavier, and Kamran Samii. “Binding of Propofol to Blood Components: Implications for Pharmacokinetics and for Pharmacodynamics.” British Journal of Clinical Pharmacology, vol. 47, no. 1, Jan. 1999, pp. 35–42. https://doi.org/10.1046/j.1365-2125.1999.00860.x 
3. Sahinovic, Marko M., et al. “Clinical Pharmacokinetics and Pharmacodynamics of Propofol.” Clinical Pharmacokinetics, vol. 57, no. 12, Dec. 2018, pp. 1539–58. https://doi.org/10.1007/s40262-018-0672-3 
4. Leeman, Mats, et al. “Proteins and Antibodies in Serum, Plasma, and Whole Blood—Size Characterization Using Asymmetrical Flow Field-Flow Fractionation (AF4).” Analytical and Bioanalytical Chemistry, vol. 410, no. 20, 2018, pp. 4867–73. https://doi.org/10.1007/s00216-018-1127-2
5. Carter, C. M. “Alterations in Blood Components.” Comprehensive Toxicology, 2018, pp. 249–93. https://doi.org/10.1016/B978-0-12-801238-3.64251-4