COMPOUND-A - SOLUBILITY IN SALINE AND OLIVE OIL - DESTRUCTION BY BLOOD

Compound A is a degradation product of sevoflurane. Knowledge of the s olubility of Compound A, CH2F-O-C(=CF2)(CF3), in blood and other solve nts would aid in the definition of its kinetics. Accordingly, we deter mined solvent/gas partition coefficients of Compound A for saline (0.1 66 +/- 0.002 [mean +/- SD; n = 4]) and olive oil (20.1 +/- 1.1 [n = 4] ) Measurement of solubility in blood was confounded by degradation of Compound A in blood and blood components. If a mixture of 99.3% saline and 0.7% oil provides the solubility equivalent to that possessed by blood (as it does for the parent compound, sevoflurane), then blood so lubility and solubility in plasma, albumin, red blood cells, or pure h emoglobin is approximately 0.31. The order of Compound A degradation w as human plasma = rat blood > whole human blood > 5% human serum album in = washed human red blood cells (hematocrit 50%) = 5% pure hemoglobi n. Presuming a solvent/gas partition coefficient of 0.31, respective a pproximate times for 50% degradation equaled 2.7, 2.8, 4.6, 9.9, 11.0, and 12 min. The accuracy of these approximations was limited by the n eed to estimate, rather than determine, the solubility of Compound A i n such solvents. Pasteurization (heating to 60 degrees C for 12 h) or pretreatment with N-ethylmaleimide (a compound that reversibly binds t o sulfhydryl groups) decreased the degradation rate in plasma. These r esults suggest that degradation arises, at least in part, from reactio n of Compound A with proteins in blood, possibly from covalent reactio n of Compound A with protein and/or from an enzymatically mediated rea ction. The products of degradation, the binding sites, and the clinica l implications of such binding and degradation remain to be determined .