To the Editor:—
In a recent article, Bernards et al. 1measured separately the flux of 3H-labelled R - and S -bupivacaine through the spinal meninges of the monkey and concluded that the meningeal permeability for the enantiomers did not differ. However, their method of calculation of the permeability coefficient does not take into account the fact that bupivacaine exists in solution as a mixture of conjugated acid (ionized) and base (unionized) forms under the chosen conditions of pH 7.4 (fig. 1).
Fig. 1. Distribution and diffusion of bupivacaine between donor and receiver compartments. The concentrations of the ionized and unionized forms of bupivacaine (symbolized as a tertiary amine R3N) in donor and receiver compartments are depicted by C1, C2, and so on.
Fig. 1. Distribution and diffusion of bupivacaine between donor and receiver compartments. The concentrations of the ionized and unionized forms of bupivacaine (symbolized as a tertiary amine R3N) in donor and receiver compartments are depicted by C1, C2, and so on.
Partial ionization complicates the calculation of the permeability coefficient. It is known for many substances, and we have shown for local anesthetics that the unionized form of the local anesthetic predominantly diffuses through the meninges, with the contribution of the ionized form being essentially negligible. 2By calculating the permeability coefficient (P [cm/min]) according to the equation
where Q = bupivacaine flux (μg/min), C = total bupivacaine concentration (= C1 + C2) in the donor reservoir (μg/ml), and A = tissue area (cm2).
Bernards et al. 1underestimate the exact value of the permeability coefficient by a factor of 6 by using the total concentration C of bupivacaine in the donor compartment (= sum of C1 + C2 in fig. 1). The actual “driving force” for diffusion of bupivacaine through the meninges (C1 ≈ 0.166C) should be calculated according the Henderson-Hasselbalch equation and the pKavalue measured by Strichartz et al. 3at 37°C.
The conclusion of this study by Bernards et al. 1is qualitatively correct; the impact of omitting the influence of ionization is nullified because R - and S -bupivacaine, having the same pKa, 4are compared. Furthermore, we independently obtained the same result using human meninges with (racemic) bupivacaine and a chiral high-pressure liquid chromatography method to measure the concurrent enantiomer concentrations individually. 5However, it needs to be reiterated that other relevant physicochemical properties, such as aqueous solubility, cannot be assumed to be equal for the enantiomers of racemic drugs separately and in the racemic admixture. 4
The results of previous studies, comparing the permeability coefficients of different drug molecules with widely differing pKavalues, and without correction for the unionized concentration, should be addressed cautiously. 6,7Future studies should address this important aspect of diffusion.
