Wasdo Scott, Juntunen Juha, Devarajan Hema, Murray Thomas, Nickels Donna, Singh Surjit, Shanks Thea, Ulmer Karen, Sloan Kenneth B
Department of Medicinal Chemistry, University of Florida, P.O. Box 100485, Gainesville, FL 32610, USA.
Eur J Pharm Sci. 2008 Aug 7;34(4-5):321-32. doi: 10.1016/j.ejps.2008.05.008. Epub 2008 Jun 5.
Do the Roberts-Sloan (RS) or modified Kasting-Smith-Cooper (KSC) equations that provide good fit to data for maximum flux, from water through mouse or human skin also provide a good fit to data for maximum fluxes through silicone membranes (polydimethylsiloxane, PDMS). The maximum fluxes through silicone membranes from water (J(MPAQ)), molecular weights (MW), solubilities in isopropyl myristate (S(IPM)) and water (S(AQ)) of 31 prodrugs and one parent drug have been fitted to the RS equation, which includes a parameter for dependence on S(AQ), and the KSC equation, which does not, to determine which equation gave the better fit. In addition, the J(MPAQ), MW, S(AQ) and solubilities in octanol (S(OCT)) of 26 diverse molecules from other laboratories were collected and fitted to the RS and KSC equations to determine if the choice of lipid parameter (S(IPM) or S(OCT)) had an effect on which equation gave the better fit. RS gave the better fit to the present prodrug database where: logJ(MPAQ)=-2.454+0.716 logS(IPM)+0.284 logS(AQ)+0.00208 MW, r(2)=0.77. RS also gave the better fit to the database from other laboratories where: logJ(MPAQ)=-2.046+0.667 logS(OCT)+0.333 logS(AQ)-0.00374 MW, r(2)=0.878 after four obvious outliers were removed to give n=22. Thus, data for J(MPAQ) can be fitted to the RS equation, which also provides the best fit to maximum flux from water through mouse or human skin and includes a dependence on S(AQ).
能很好拟合水透过小鼠或人体皮肤的最大通量数据的罗伯茨 - 斯隆（RS）方程或修正的卡斯汀 - 史密斯 - 库珀（KSC）方程，对于水透过硅酮膜（聚二甲基硅氧烷，PDMS）的最大通量数据是否也能很好拟合呢？已将31种前体药物和1种母体药物从水透过硅酮膜的最大通量（J(MPAQ)）、分子量（MW）、在肉豆蔻酸异丙酯中的溶解度（S(IPM)）以及在水中的溶解度（S(AQ)）代入RS方程（其中包括一个依赖于S(AQ)的参数）和KSC方程（其中不包括该参数），以确定哪个方程拟合得更好。此外，收集了来自其他实验室的26种不同分子的J(MPAQ)、MW、S(AQ)以及在辛醇中的溶解度（S(OCT)），并代入RS和KSC方程，以确定脂质参数（S(IPM)或S(OCT)）的选择对哪个方程拟合得更好是否有影响。RS对当前前体药物数据库拟合得更好，其中：logJ(MPAQ)= -2.454 + 0.716 logS(IPM) + 0.284 logS(AQ) + 0.00208 MW，r(2)=0.77。在去除4个明显异常值（使n = 22）后，RS对来自其他实验室的数据库拟合也更好，其中：logJ(MPAQ)= -2.046 + 点击显示完整内容0.667 logS(OCT) + 0.333 logS(AQ) - 0.00374 MW，r(2)=0.878。因此，J(MPAQ)的数据可以用RS方程拟合，该方程对水透过小鼠或人体皮肤的最大通量也提供了最佳拟合，并且包括对S(AQ)的依赖关系。
