School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY, USA.
Division of Theoretical Physics, Physics Department, Aristotle University of Thessaloniki, Thessaloniki, Greece; Pharma Informatics Unit, Research Center ATHENA, Athens, Greece.
Eur J Pharm Sci. 2019 Mar 15;130:137-146. doi: 10.1016/j.ejps.2019.01.027. Epub 2019 Jan 25.
This work aims to explore the unphysical assumptions associated with i) the homogeneity of the well mixed compartments of pharmacokinetics and ii) the diffusion limited model of drug dissolution. To this end, we i) tested the homogeneity hypothesis using Monte Carlo simulations for a reaction and a diffusional process that take place in Euclidean and fractal media, ii) re-considered the flip-flop kinetics assuming that the absorption rate for a one-compartment model is governed by an instantaneous rate coefficient instead of a rate constant, and, iii) re-considered the extent of drug absorption as a function of dose using an in vivo reaction limited model of drug dissolution with integer and non-integer stoichiometry values. We found that drug diffusional processes and reactions are slowed down in heterogeneous media and the environmental heterogeneity leads to increased fluctuations of the measurable quantities. Highly variable experimental literature data with measurements in intrathecal space and gastrointestinal fluids were explained accordingly. Next, by applying power law and Weibull input functions to a one-compartment model of disposition we show that the shape of concentration-time curves is highly dependent on the time exponent of the input functions. Realistic examples based on PK data of three compounds known to exhibit flip-flop kinetics are analyzed. The need to use time dependent coefficients instead of rate constants in PBPK modeling and virtual bioequivalence is underlined. Finally, the shape of the fraction absorbed as a function of dose plots, using an in vivo reaction limited model of drug dissolution were found to be dependent on the stoichiometry value and the solubility of drug. Ascending and descending limbs were observed for the higher stoichiometries (2.0 and 1.5) with the low solubility drug. In contrast, for the more soluble drug, a continuous increase of fraction absorbed as a function of dose is observed when the higher stoichiometries are used (2.0 and 1.5). For both drugs, the fraction absorbed for the lower values of stoichiometry (0.7 and 1.0) exhibit a non-dependency on dose profile. Our results give an insight into the complex picture of in vivo drug dissolution since diffusion-limited and reaction-limited processes seem to operate under in vivo conditions concurrently.
i）药代动力学中均匀混合隔室的假设，以及 ii）药物溶解的扩散限制模型。为此，我们 i）通过在欧几里得和分形介质中进行反应和扩散过程的蒙特卡罗模拟来测试均匀性假设，ii）重新考虑翻转动力学假设，假设单隔室模型的吸收速率由瞬时速率系数而不是速率常数控制，以及，iii）重新考虑药物吸收程度作为剂量的函数，使用具有整数和非整数化学计量值的体内反应限制药物溶解模型。我们发现，药物扩散过程和反应在非均匀介质中会减慢，环境非均匀性会导致可测量量的波动增加。高度可变的实验文献数据，包括在鞘内空间和胃肠道液中的测量数据，都得到了相应的解释。接下来，通过将幂律和 Weibull 输入函数应用于处置的单隔室模型，我们表明浓度-时间曲线的形状高度依赖于输入函数的时间指数。基于已知具有翻转动力学的三种化合物的 PK 数据进行了实际分析。强调了在 PBPK 建模和虚拟生物等效性中使用时间依赖系数而不是速率常数的必要性。最后，使用体内反应限制药物溶解模型，发现作为剂量函数的吸收分数的形状取决于化学计量值和药物的溶解度。对于高化学计量值（2.0 和 1.5）和低溶解度药物，观察到上升和下降支。相比之下，对于更易溶解的药物，当使用更高的化学计量值（2.0 和 1.5）时，观察到吸收分数作为剂量的连续增加。对于两种药物，化学计量值较低（0.7 和 1.0）的吸收分数与剂量曲线无关。我们的结果深入了解了体内药物溶解的复杂情况，因为扩散限制和反应限制过程似乎在体内条件下同时起作用。
