Hsu Cheng-Hsuan, Jay Michael, Bummer Paul M, Lehmler Hans-Joachim
Division of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky 40536, USA.
Pharm Res. 2003 Jun;20(6):918-25. doi: 10.1023/a:1023899505837.
It has been suggested that fluorocarbon liquid may be a unique vehicle for the delivery of drugs directly to the acutely injured lung. A prodrug approach was used as a means of enhancing the solubility of a model drug (nicotinic acid) in the fluorocarbon. The solubility, the chemical stability of the putative prodrugs, and the sensitivity to enzymatic hydrolysis was investigated.
The solubility of each nicotinic acid ester was determined in buffer as a function of pH and in perflubron. The octanol/buffer partition coefficient was determined at pH 7.4. The chemical stability of the putative prodrugs was determined as a function of pH, temperature, buffer content, and ionic strength. In addition, sensitivity of the esters to enzymatic degradation was evaluated.
Compared with nicotinic acid, the solubility in perflubron of the esters was significantly enhanced. In aqueous buffers, the esters exhibited pseudo-first order degradation kinetics, with both acid and base catalyzed loss. Studies of the fluorobutyl ester indicate quantitative loss of the putative prodrug and release of the parent nicotinic acid. Porcine esterase accelerated the loss of fluorobutyl ester by a factor of over 200 compared with chemical hydrolysis at pH 7.4.
The properties of the fluorinated esters suggest that they may be suitable candidates for further testing as possible prodrugs of nicotinic acid based upon higher solubility in perflubron, rapid release of the parent drug after simple hydrolysis, and sensitivity to the presence of a model esterase enzyme.
有人提出氟碳液体可能是将药物直接递送至急性损伤肺的独特载体。采用前药方法来提高模型药物（烟酸）在氟碳中的溶解度。研究了推定前药的溶解度、化学稳定性以及对酶促水解的敏感性。
测定每种烟酸酯在缓冲液中作为pH的函数以及在全氟溴烷中的溶解度。在pH 7.4下测定辛醇/缓冲液分配系数。测定推定前药的化学稳定性作为pH、温度、缓冲液含量和离子强度的函数。此外，评估酯对酶促降解的敏感性。
与烟酸相比，酯在全氟溴烷中的溶解度显著提高。在水性缓冲液中，酯表现出准一级降解动力学，存在酸催化和碱催化的损失。氟丁酯的研究表明推定前药定量损失，母体烟酸释放。与pH 7.4下的化学水解相比，猪酯酶使氟丁酯的损失加快了200多倍。
氟化酯的性质表明，基于在全氟溴烷中的较高溶解度、简单水解后母体药物的快速释放以及对模型酯酶存在的敏感性，它们可能是作为烟酸可能前药进行进一步测试的合适候选物。
