Fukumura K, Yamaoka K, Higashimori M, Nakagawa T
Graduate School of Pharmaceutical Science, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
J Pharm Sci. 1999 May;88(5):538-43. doi: 10.1021/js9803757.
A curve-fitting program based on the Finite Element Method, MULTI(FEM), was developed to model nonlinear local disposition of a drug in the liver under non-steady-state conditions. The program was written in FORTRAN on an IBM-compatible personal computer. The validity of MULTI(FEM) was confirmed by analyzing the outflow kinetics of oxacillin (a model drug) following a pulse input to isolated, perfused rat livers, according to both linear and nonlinear dispersion models. Four dose levels (300, 1000, 3000, and 5000 microg) of oxacillin were administered to observe the dose-dependency in the hepatic local disposition. First, the individual outflow time-profiles at the same dose were averaged, and the average time-profile was analyzed by MULTI(FEM) based on linear dispersion models to yield a single curve fit. The fitted parameters at each dose level were compared with parameters estimated using MULTI(FILT), a program based on fast inverse Laplace transform, to analyze linear pharmacokinetics. The estimated parameters by MULTI(FEM) were in good agreement with those by MULTI(FILT). The apparent elimination rate constant (ke) decreased with an increase in dose, whereas other parameters showed no discernible dependency on an increase of dose. Second, the average outflow time-profiles at the four dose levels were simultaneously analyzed by MULTI(FEM) based on dispersion models featuring Michaelis-Menten elimination. The outflow time-profiles of oxacillin were well approximated by a two-compartment dispersion model with central Michaelis-Menten elimination. The maximum elimination rate constant (Vmax) and the Michaelis constant (Km) were estimated to be 1520 microg/mL/min and 41.3 microg/mL, respectively. Thus, the capability of MULTI(FEM) was demonstrated in evaluating capacity-limited local disposition in the liver.
开发了一种基于有限元法的曲线拟合程序MULTI(FEM)，用于模拟非稳态条件下药物在肝脏中的非线性局部处置。该程序用FORTRAN语言编写，运行于IBM兼容个人计算机上。通过根据线性和非线性弥散模型分析脉冲输入到离体灌注大鼠肝脏后苯唑西林（一种模型药物）的流出动力学，证实了MULTI(FEM)的有效性。给予四个剂量水平（300、1000、3000和5000微克）的苯唑西林，以观察肝脏局部处置中的剂量依赖性。首先，对相同剂量下的个体流出时间曲线进行平均，并基于线性弥散模型用MULTI(FEM)分析平均时间曲线，以得到单曲线拟合。将每个剂量水平下的拟合参数与使用基于快速拉普拉斯逆变换的程序MULTI(FILT)估计的参数进行比较，以分析线性药代动力学。MULTI(FEM)估计的参数与MULTI(FILT)估计的参数高度一致。表观消除速率常数(ke)随剂量增加而降低，而其他参数未显示出对剂量增加有明显依赖性。其次，基于具有米氏消除的弥散模型，用MULTI(FEM)同时分析四个剂量水平下的平均流出时间曲线。苯唑西林的流出时间曲线可用具有中央米氏消除的二室弥散模型很好地近似。最大消除速率常数(Vmax)和米氏常数(Km)估计分别为1520微克/毫升/分钟和41.3微克/毫升。因此，证明了MULTI(FEM)在评估肝脏中容量限制型局部处置方面的能力。
