Thermodynamics of partitioning of phenothiazine drugs between phosphatidylcholine bilayer vesicles and water studied by second-derivative spectrophotometry

Abstract

The partition coefficients (Kps) of phenothiazine drugs (trifluoperazine, triflupromazine, chlorpromazine and promazine) between phosphatidylcholine (PC) small unilamellar vesicles (SUV) and water were determined over the temperature range of 10-40°C by a second-derivative spectrophotometric method. The second derivative spectra of each drug solution containing various amounts of SUV showed distinct derivative isosbestic points confirming the entire elimination of the residual background signal effects of the SUV. The Kp values were calculated from the derivative intensity change of the drugs induced by the addition of SUV to the drug buffer solutions (pH 7.4) and obtained with the R.S.D. below 10% (n=3). The van't Hoff analysis of the temperature dependence of Kp values revealed negative ΔHw→l and positive ΔSw→l, suggesting an enthalpy/entropy driven mechanism for the phenothiazine partitioning. The negative ΔHw→l implies that the electrostatic interaction, positively charged alkyl amino groups of phenothiazine drugs with negatively charged phosphate groups on the surface of PC SUV, partly contributes to the partitioning. The existence of halogen atom(s) on the phenothiazine ring at position C-2 enhanced the Kp value (H