Fitting the blood-to-plasma or plasma-to-blood ratios

Why to fit the ratio curves?

The plasma must be separated from blood, and the radioactivity and mass of both plasma and blood samples (or the precipitant left in the tube after most of plasma is removed) must be measured. Radioactivity measurement is hampered by the fast decay of radioactivity, especially with C-11 labelled radiopharmaceuticals. Fitting of a mathematical function to the measured ratios reduces variation and enables interpolation and extrapolation of the ratio curve, for the conversion of blood TAC to plasma.

Individually fitted ratios can be applied in the conversion of blood TAC to plasma using taccalc, but often a population mean curve is determined and implemented in programs b2plasma and p2blood.

The plasma-to-blood and blood-to-plasma ratio curves can be very different for different radiotracers, requiring development of a model of its own for each radiotracer, or empirically selecting a suitable function.

Erythrocytes (red blood cells, RBCs) are the main cellular component of blood, and the concentration difference between plasma and blood is dependent on partitioning of radiopharmaceutical and its labelled metabolites between water spaces in plasma and RBCs, and the rate of transport across RBC membrane. Binding to plasma proteins has major impact on the distribution, as well as binding to RBC proteins (mainly haemoglobin). RBC-to-plasma ratio (rRBC/P) as function of time determines the blood-to-plasma ratio, but concentrations can be directly measured only from plasma and blood samples, not from RBCs. RBC-to-plasma ratio can be converted to plasma-to-blood ratio with equation

, where HCT is the haematocrit. Plasma-to-blood ratio is preferred to blood-to-plasma ratio, because divider is not zero if either plasma or RBCs contain any radioactivity. Most radiotracers are administered intravenously into the plasma space, and in that case RBC-to-plasma ratio at zero time is zero, and plasma-to-blood ratio is only dependent on the haematocrit:

This is also the maximum value that the plasma-to-blood curve can get at any time point. In the opposite case, if practically all radioactivity is found in RBCs ([15O]CO, [15O]O2), rRBC/P is very high, and then rP/B approaches zero. HCT cannot be much higher than 0.5, and thus rP/B must be between 0 and ∼2.

How to fit the ratio curves?

After intravenous administration, radiotracer immediately starts to form equilibrium with the constituents of the blood, and at least partial equilibrium is achieved before bolus reaches the blood sampling site. While radiolabelled metabolites usually appear in the blood at sampling site only after one full circulation, requiring a delay time term in functions and models for fraction of metabolites in plasma, the delay time term is not needed in functions for RBC-to-plasma ratio.

Models

Time-dependent plasma-to-blood ratio can be described using compartmental models. For instance, Lee et al (2008) proposed a simple model for [18F]FDG rat studies. Asselin et al (2002) developed a unified compartment model for 6-[18F]fluoro-L-meta-tyrosine and its metabolites in blood and partitioning between plasma and blood cells.

Measurement of rapid concentration changes in blood and plasma soon after radiotracer administration is difficult and prone to sampling and timing errors. Unfortunately the modelling of radiotracer kinetics between plasma and blood cells has reached little attention, and in most studies only simplistic empiric functions, at best, have been applied to the data.

Functions

The rRBC/P curve could be described with variable functions. Simulated rRBC/P curves based on surge function with recirculation are shown in Figure 1 (left side), and plasma-to-blood ratios calculated from the same curves are shown on the right side of the figure.

Example RBC-to-plasma ratios, represented with surge function plus recirculation Example plasma-to-blood ratios, represented with surge function plus recirculation
Figure 1. On the left, functions representing typical RBC-to-plasma ratios. On the right, the same functions converted to plasma-to-blood ratios, using HCT=0.45. Simulations are stored in GitLab.
The initial phase of radiotracer uptake into RBC (decrease in plasma-to-blood ratio) can be very rapid (see the purple curve). This can pass unnoticed in PET studies because of limited blood samples and continued plasma-to-RBC transport in blood sample tubes.

Rational functions can be used to represent rRBC/P curves. Examples are shown in Figure 2 (left side), and plasma-to-blood ratios calculated from the same curves are shown on the right side of the figure.

Example RBC-to-plasma ratios, represented with rational function Example plasma-to-blood ratios, calculated from rational functions for RBC-to-plasma ratios
Figure 2. On the left, rational functions representing typical RBC-to-plasma ratios. On the right, the same functions converted to plasma-to-blood ratios, using HCT=0.45.

Edison et al (2009) used extended Hill (sigmoidal) function for fitting [11C]PIB plasma-to-blood ratios (rP/Bs), and Bloomfield et al (2016) applied it to [11C]PBR28:

, where p1 < 0, and t is normalised time (sample time divided by study length, thus t < 1). Function value approaches 1 at very small t, which means that concentration in blood cells at administration time is assumed to be the same as in plasma.

Similar function was used to fit blood-to-plasma ratio curves by Tarkia et al (2012):

Exponential or two-exponential function with constant term has sometimes been used for fitting plasma-to-blood or blood-to-plasma ratio curves (Lee et al., 2008; Wu et al., 2016).


Software

Applications fit_bpr and fit_sigm may be useful in fitting functions to blood-to-plasma or RBC-to-plasma ratio data. Plasma-to-blood ratio data may be fitted using fit_pbr.

Function parameters

Function parameters are saved into specific fit file format, which are ASCII text files.

Program fit2dat can be used to calculate the fitted ratio curve for converting blood-to-plasma or vice versa using taccalc , or for other purposes such as drawing graphs.


See also:



References

Asselin M-C, Wahl LM, Cunningham VJ, Amano S, Nahmias C. In vivo metabolism and partitioning of 6-[18F]fluoro-L-meta-tyrosine in whole blood: a unified compartment model. Phys Med Biol. 2002; 47: 1961-1977. doi: 10.1088/0031-9155/47/11/309.

Lee J-S, Su K-H, Lin J-C, Chuang Y-T, Chueh H-S, Liu R-S, Wang S-J, Chen J-C. A novel blood-cell-two-compartment model for transferring a whole blood time activity curve to plasma in rodents. Comput Methods Programs Biomed. 2008; 92(3): 299-304. doi: 10.1016/j.cmpb.2008.02.006.



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Updated at: 2019-05-25
Created at: 2016-04-06
Written by: Vesa Oikonen