I read the study by Liu and Eckenhoff1with much interest. The authors investigated the binding of isoflurane and enflurane with human serum albumin with isothermal titration calorimetry and calculated the molecular properties of the two anesthetics using molecular analysis software. They concluded that weak polar interactions confer considerable selectivity and that differences in drug action may arise from occupancy of different protein sites. However, I believe that there are some problems drawing these conclusions from this study.

The authors assumed that the different manners of isoflurane and enflurane binding to their binding sites in human serum albumin can be attributed to their different dipole moments. However, this seems untrue. If the selectivity of binding sites to accommodate anesthetic molecules depends on the dipole moments of the drugs, how can we explain the different potencies of optically pure stereoisomers? The size of the dipole moments of the stereoisomes must be the same; however, it is known that the (+) isomer of isoflurane is more potent than the (−) isomer (minimum alveolar concentration = 1.06 ± 0.07% vs.  1.62 ± 0.02%).2I assume that optical isomers exert their different anesthetic effects via  different manners of binding to their receptor sites. I hope that the authors can prove that only one of the optical isomers, presumably not both of them, can bind to the site of human serum albumin using optically pure isoflurane isomers.3 

Dipole moment is a very useful concept with which to express the asymmetry in the molecular charge distribution; however, it is too simple as an indicator to express the characteristics of chemical substances. I believe that interaction between anesthetic molecules and their binding sites must be far more complex than can be explained by dipole–dipole interactions.

Tokyo Medical and Dental University, School of Medicine, Tokyo, Japan. ishikawa.mane@tmd.ac.jp

Liu R, Eckenhoff RG: Weak polar interactions confer albumin binding site selectivity for haloether anesthetics. Anesthesiology 2005; 102:799–805
Lysko GS, Robinson JL, Casto R, Ferrone RA: The stereospecific effects of isoflurane isomers in vivo. Eur J Pharmacol 1994; 263:25–9
Huang CG, Rozov LA, Halpern DF, Vernice GG: Preparation of isoflurane enantiomers: A first step toward understanding the mechanism of anesthesia. J Org Chem 1993; 58:7382–7