Beall H D, Sloan K B
Department of Pharmaceutical Sciences, The University of Montana, 32 Campus Drive #1552, Missoula, Montana 59812-1552, USA.
Int J Pharm. 2001 Apr 17;217(1-2):127-37. doi: 10.1016/s0378-5173(01)00609-3.
The solubilities in isopropyl myristate (SIPM) and pH 4.0 buffer (SAQ) and the partition coefficients between IPM and pH 4.0 buffer (KIPM:AQ) have been measured for a series of 3-alkylcarbonyl-5-fluorouracil prodrugs (3-AC-5-FU). The 3-AC-5-FU prodrugs were all 100 times more soluble in IPM and the first two members of the series were also more soluble in pH 4.0 buffer than 5-FU. The abilities of the 3-AC-5-FU prodrugs to deliver total 5-FU species through hairless mouse skin from IPM suspensions (Ji) were also measured. The 3-propionyl derivative 3, which exhibited the highest SAQ in the series, gave the highest Ji value. The SIPM, SAQ and molecular weights (mw) of the 3-AC-5-FU series correctly predicted the rank order and very closely (0.10 log units) predicted the absolute values for logJi using the transformed Potts-Guy equation. Although the series of 3-AC-5-FU prodrugs was generally quite effective at increasing Ji (2-20 times), the best 3-AC-5-FU prodrug was not as effective as the best 1-alkylcarbonyl-5-FU prodrug (1-AC-5-FU) at increasing Ji and the ability of the 3-AC-5-FU prodrugs to increase the concentration of total 5-FU species in the skin was 2-5 times less than the 1-AC-5-FU prodrugs. Thus, the 1-AC-5-FU prodrugs remain as the best prodrugs with which to enhance the topical delivery of 5-FU.
已测定了一系列3-烷基羰基-5-氟尿嘧啶前药（3-AC-5-FU）在肉豆蔻酸异丙酯（SIPM）和pH 4.0缓冲液（SAQ）中的溶解度以及在IPM和pH 4.0缓冲液之间的分配系数（KIPM:AQ）。所有3-AC-5-FU前药在IPM中的溶解度均比5-氟尿嘧啶高100倍，且该系列的前两个成员在pH 4.0缓冲液中的溶解度也比5-氟尿嘧啶高。还测定了3-AC-5-FU前药从IPM悬浮液通过无毛小鼠皮肤递送总5-氟尿嘧啶物质的能力（Ji）。该系列中SAQ最高的3-丙酰基衍生物3给出了最高的Ji值。3-AC-5-FU系列的SIPM、SAQ和分子量（mw）正确预测了排名顺序，并使用变换后的Potts-Guy方程非常接近地（0.10对数单位）预测了logJi的绝对值。尽管3-AC-5-FU前药系列在提高Ji方面通常相当有效（2至20倍），但最佳的3-AC-5-FU前药在提高Ji方面不如最佳的1-烷基羰基-5-氟尿嘧啶前药（1-AC-5-FU）有效，并且3-AC-5-FU前药增加皮肤中总5-氟尿嘧啶物质浓度的能力比1-AC-5-FU前药低2至5倍。因此，1-AC-5-FU前药仍然是增强5-氟尿嘧啶局部递送的最佳前药。
