Physicochemical and Hydrolytic Characteristics of Phenytoin Derivatives
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概要
- 論文の詳細を見る
To further clarify the pharmacokinetic characteristics of phenytoin (DPH) and its derivatives, DPH-1-methylnicotininate (MNDPH), valeroyl DPH (VADPH) and valproyl DPH (VPDPH), in plasma and brain, we have investigated their physicochemical properties and protein binding characteristics. Additionally, the hydrolytic conversion of these derivatives to DPH was also studied using small intestine, liver and brain tissues, as well as rat plasma. The log partition coefficient (PC) values of all derivatives were much higher than that of DPH. Judging from their pK_a values (5.68 and 5.91 for VADPH and VPDPH, respectively) and pH-solubilities, VADPH and VPDPH were acidic compounds, while MNDPH was basic. These data indicated that most fractions of VADPH and VPDPH existed as an ionized form (these fractions existed in an ionized form, 0.98 and 0.97,respectively) at physiological pH, whereas MNDPH existed as a unionized form under the same conditions. Rosenthal or Scatchard plots of the binding data of DPH and its derivatives to both rat plasma protein and bovine serum albumin (BSA) exhibited straight lines over their concentration ranges used, indicating that DPH and its derivatives have a single binding site on the protein. The binding potencies (K or n・P_1 value) of the derivatives to both proteins were much greater than that of DPH. No DPH produced from VADPH and VPDPH was found in the biological fluids over a period of 24 h. However, the hydrolysis of MNDPH to DPH was observed in plasma and the tissues used, with the most rapid hydrolysis in the small intestine, and the hydrolysis rate constant in plasma was ca. 20-fold greater than that in the brain. The present results lead us to propose that the low uptake of VADPH and VPDPH into the brain, as well as their rapid elimination from plasma is mainly ascribed to both the high protein binding and the large dissociation of derivatives in the plasma, compared with that of DPH.
- 社団法人日本薬学会の論文
- 1994-10-15
著者
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岩城 正宏
近畿大学薬学部
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岩城 正宏
近畿大薬学部
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小木曽 太郎
Faculty of Pharmaceutical Sciences, Kinki University
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岩城 正宏
Faculty of Pharmaceutical Sciences, Kinki University
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谷野 公俊
近畿大薬学部
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田辺 元三
近畿大学薬学部
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谷野 公俊
Faculty of Pharmaceutical Sciences, Kinki University
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村岡 修
Faculty of Pharmaceutical Sciences, Kinki University
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田辺 元三
Faculty of Pharmaceutical Sciences, Kinki University
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村岡 修
Faculty Of Pharmaceutical Sciences Kinki University
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田邉 元三
近畿大薬
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小木曽 太郎
近畿大学 薬学部
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Tanino T
Kinki Univ. Osaka Jpn
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小木曽 太郎
近畿大 薬
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村岡 修
近畿大薬:近畿大薬総研
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