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LETTER TO THE EDITOR |
Biomedical Mass Spectrometry Laboratory
General Clinical Research Center
University of Florida
PO Box 100322
Gainesville, FL 32611-0322
E-mail: epq{at}ufl.edu
Dear Sir:
In a recent issue of the Journal, Pietrzik et al (1) described a model for calculating the appearance and elimination kinetics of red blood cell (RBC) folate. However, the authors made several erroneous assumptions in deriving this model.
The pharmokinetic principle on which their model is based is valid only for reactions that follow first-order kinetics (eg, radioactive decay) in which the analyte concentration halves every half-life—eg, 1/2 remains after 1 half-life, 1/4 remains after 2 half-lives, and so on. However, RBC turnover does not follow first-order kinetics. Instead, each cell has a finite life span, and the cells are removed from circulation after 13–21 wk (mean: 
17 wk) (2). This phenomenon was aptly illustrated by Lin et al (3) who, after administering a single dose of [14C]folic acid, showed that the loss of RBC [14C]folate occurred primarily between the 13th and 21st wk after administration of the label and that a mean RBC residency of labeled folate was 16 wk. Thus, after 12 wk (the equivalent of 1.5 so-called "half-lives"), nearly all of the RBCs produced on day 1 would be intact—compared with only 35% (0.51.5) that would be predicted if the reaction followed first-order kinetics. Moreover, after 20 wk (2.5 half-lives), none of the day 1 RBCs should remain—compared with 18% (0.52.5) that would be predicted by first-order kinetics. The fact that RBC folate does not obey first-order kinetics was also reported in the 1960s by Herbert (4), who showed that RBC concentrations decreased linearly in a subject consuming a severely folate-deficient diet (5 µg folate acid/d) and reached a minimum (10 ng/mL) after 18 wk depletion.
Circulating blood (2) contains a mixture of RBCs of different ages (0 to 17 wk). Thus, when discussing RBCs, the term "half-life" refers to the fact that, after one half-life (8.5 wk), roughly one-half of the original RBC population (the older RBCs) will no longer be in circulation (replaced by new RBCs). Thus, the turnover of an RBC population is linear (ie, all of the RBCs are replaced every 2 half-lives), whereas the change in population resulting from a first-order reaction would be exponential.
Moreover, Pietrzik et al (1) assumed that the RBC folate concentration had not reached a maximum after 24 wk of fortification. However, because no samples were collected after 24 wk, it is not possible to determine whether the RBC folate concentration increased after this period or whether it reached a plateau between 16 and 24 wk. Because the maximum life span of RBCs is 21 wk (2), it should take at least that long for RBC folate concentrations to plateau. However, plateau RBC folate enrichment may be further delayed by the amount of time it takes for the RBC progenitor cells, presumably in the bone marrow, to reach maximum enrichment. The rate at which RBC folate concentrations increase is also a function of the rate at which the progenitor cells become folate enriched.
In conclusion, because RBC production and loss do not follow first-order kinetics, a pharmokinetic model based on first-order kinetics cannot be used to predict the appearance of folate in the RBCs and its elimination from the RBCs. Therefore, there is no scientific basis for the model reported by Pietrzik et al (1).
ACKNOWLEDGMENTS
The author had no personal or financial conflict of interest.
REFERENCES
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