Kodaira Hiroshi, Kusuhara Hiroyuki, Fuse Eiichi, Ushiki Junko, Sugiyama Yuichi
Graduate School of Pharmaceutical Sciences, the University of Tokyo, Tokyo (H.Ko., H.Ku.); Pharmacokinetic Research Laboratories, Research Division, Kyowa Hakko Kirin Co., Ltd., Shizuoka (H.Ko., E.F., J.U.); and Sugiyama Laboratory, RIKEN Innovation Center, RIKEN Research Cluster for Innovation, RIKEN (Y.S.), Kanagawa, Japan.
Drug Metab Dispos. 2014 Jun;42(6):983-9. doi: 10.1124/dmd.113.056606. Epub 2014 Mar 18.
A pharmacokinetic model was constructed to explain the difference in brain- and cerebrospinal fluid (CSF)-to-plasma and brain-to-CSF unbound drug concentration ratios (Kp,uu,brain, Kp,uu,CSF, and Kp,uu,CSF/brain, respectively) of drugs under steady-state conditions in rats. The passive permeability across the blood-brain barrier (BBB), PS1, was predicted by two methods using log(D/molecular weight(0.5)) for PS1(1) or the partition coefficient in octanol/water at pH 7.4 (LogD), topologic van der Waals polar surface area, and van der Waals surface area of the basic atoms for PS1(2). The coefficients of each parameter were determined using previously reported in situ rat BBB permeability. Active transport of drugs by P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) measured in P-gp- and Bcrp-overexpressing cells was extrapolated to in vivo by introducing scaling factors. Brain- and CSF-to-plasma unbound concentration ratios (Kp,uu,brain and Kp,uu,CSF, respectively) of 19 compounds, including P-gp and Bcrp substrates (daidzein, dantrolene, flavopiridol, genistein, loperamide, quinidine, and verapamil), were simultaneously fitted to the equations in a three-compartment model comprising blood, brain, and CSF compartments. The calculated Kp,uu,brain and Kp,uu,CSF of 17 compounds were within a factor of three of experimental values. Kp,uu,CSF values of genistein and loperamide were outliers of the prediction, and Kp,uu,brain of dantrolene also became an outlier when PS1(2) was used. Kp,uu,CSF/brain of the 19 compounds was within a factor of three of experimental values. In conclusion, the Kp,uu,CSF/brain of drugs, including P-gp and Bcrp substrates, could be successfully explained by a kinetic model using scaling factors combined with in vitro evaluation of P-gp and Bcrp activities.
构建了一个药代动力学模型，以解释大鼠稳态条件下药物的脑-血浆、脑脊液（CSF）-血浆以及脑-脑脊液未结合药物浓度比（分别为Kp,uu,brain、Kp,uu,CSF和Kp,uu,CSF/brain）的差异。采用两种方法预测血脑屏障（BBB）的被动通透性PS1，方法1使用PS1的log(D/分子量(0.5))，方法2使用pH 7.4时在正辛醇/水中的分配系数（LogD）、拓扑范德华极性表面积以及碱性原子的范德华表面积。利用先前报道的大鼠原位BBB通透性确定每个参数的系数。通过引入比例因子，将在P-糖蛋白（P-gp）和乳腺癌耐药蛋白（Bcrp）过表达细胞中测得的药物经P-gp和Bcrp的主动转运外推至体内。将包括P-gp和Bcrp底物（大豆苷元、丹曲林、黄酮哌啶醇、染料木黄酮、洛哌丁胺、奎尼丁和维拉帕米）在内的19种化合物的脑-血浆和脑脊液-血浆未结合浓度比（分别为Kp,uu,brain和Kp,uu,CSF）同时拟合到包含血液、脑和脑脊液隔室的三室模型方程中。计算得到的17种化合物的Kp,uu,brain和Kp,uu,CSF在实验值的三倍范围内。染料木黄酮和洛哌丁胺的Kp,uu,CSF值是预测的异常值，当使用PS1(2)时，丹曲林的Kp,uu,brain也成为异常值。19种化合物的Kp,uu,CSF/brain在实验值的三倍范围内。总之，使用比例因子结合P-gp和Bcrp活性的体外评估的动力学模型能够成功解释包括P-gp和Bcrp底物在内的药物的Kp,uu,CSF/brain。
