Thermodynamics of Partitioning of Phenothiazine Drugs between Phosphatidylcholine Bilayer Vesicles and Water Studied by Second-Derivative Spectrophotometry

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概要

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• The partition coefficients (K_ps) 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℃ 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 K_p 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 K_p values revealed negative ΔH_<w→1> and positive ΔS_<w→1> suggesting an enthalpy/entropy driven mechanism for the phenothiazine partitioning. The negative ΔH_<w→1> 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 K_p value (H<Cl<CF_3). This enhancement can be accounted for by an increase in the ΔS_<w→1> value (H<Cl<CF_3), and the ΔS_<w→1> increase is considered to be enhancement of disorder in the hydrophobic acyl chain regions of PC SUV membranes derived from the phenothiazine ring insertion and thus depends on the bulkiness of the substituent. The enthalpy-entropy correlation analysis yielding a good linear relationship also suggests that the phenothiazine drugs studied have identically an enthalpy-entropy compensation mechanism for the partitioning.

• 公益社団法人日本薬学会の論文
• 2003-09-01

著者

• 北村 和則

  富山化学工業株式会社綜合研究所

• Kitamura Keisuke

  Kyoto Pharmaceutical University

• KITADE Tatsuya

  Kyoto Pharmaceutical University

• TAKEGAMI Shigehiko

  Kyoto Pharmaceutical University

• Kitamura K

  Kyoto Pharmaceutical University

• KITAGAWA Ai

  Kyoto Pharmaceutical University

• KAWAMURA Kikuko

  Kyoto Pharmaceutical University

• 北村 和則

  Kyoto Pharmaceutical University

• Kitamura Keisuke

  Kyoto College of Pharmacy

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