Nakai D, Fuse E, Suzuki H, Inaba M, Sugiyama Y
Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
J Drug Target. 1996;3(6):443-53. doi: 10.3109/10611869609015964.
Antitumor drugs can be classified into two groups; cell cycle phase nonspecific (type I) and specific (type II) drugs. The cytotoxic activity of type I drugs depends on the time-concentration product (AUC), whereas that of type II drugs is time-dependent. Therefore, not only the AUC in the target organ, but also the exposure time is an important factor for evaluating the efficiency of any delivery system for antitumor drugs. In the present study, we examined the factors governing the cytotoxicity of drugs in tumors based on a hybrid perfusion model. It is suggested that the increase in tumor tissue binding of drug results in an increased unbound drug mean residence time (MRTT,U), leading to the increased activity of type II drugs. In contrast, the cytotoxic activity of type I drugs is unaffected by the alteration in the tissue binding since the intracellular AUC defined for unbound drugs (AUCT,U) is unaffected by the extent of drug binding. We also found that the symmetrical increase in the permeability-surface area products (PS) for drug influx (PSinf) and efflux (PSeff) across the tumor plasma membrane results in the unaltered and reduced antitumor activity for the type I and type II drugs, respectively, due to the unaltered AUCT,U and to the reduced MRTT,U. The kinetic analysis suggests that the increase in PSinf/PSeff ratio results in the increased cytotoxic activity of both type I and type II drugs. Collectively, optimization of the antitumor activity can be attained by increasing the tissue binding for type II drugs and by increasing PSinf and/or by decreasing PSeff type I and type II drugs. The present simulation study was carried out by considering the pharmacodynamic features of antitumor drugs and was a method of predicting how the antitumor activity may change on altering each process (tissue binding and membrane permeability for the influx and efflux processes) which governs the characteristics of drug distribution to tumors.
细胞周期非特异性（I型）和特异性（II型）药物。I型药物的细胞毒性活性取决于时间-浓度乘积（AUC），而II型药物的细胞毒性活性则与时间相关。因此，不仅靶器官中的AUC，而且暴露时间也是评估任何抗肿瘤药物递送系统效率的重要因素。在本研究中，我们基于混合灌注模型研究了影响肿瘤中药物细胞毒性的因素。有人提出，药物在肿瘤组织中的结合增加会导致未结合药物平均驻留时间（MRTT,U）增加，从而导致II型药物活性增加。相比之下，I型药物的细胞毒性活性不受组织结合变化的影响，因为未结合药物定义的细胞内AUC（AUCT,U）不受药物结合程度的影响。我们还发现，药物跨肿瘤质膜的流入（PSinf）和流出（PSeff）的通透表面积乘积（PS）对称增加，分别导致I型和II型药物的抗肿瘤活性不变和降低，这是由于AUCT,U不变和MRTT,U降低所致。动力学分析表明，PSinf/PSeff比值的增加导致I型和II型药物的细胞毒性活性增加。总的来说，通过增加II型药物的组织结合以及增加I型和II型药物的PSinf和/或降低PSeff，可以实现抗肿瘤活性的优化。本模拟研究是通过考虑抗肿瘤药物的药效学特征进行的，是一种预测在改变控制药物向肿瘤分布特征的每个过程（组织结合以及流入和流出过程的膜通透性）时抗肿瘤活性如何变化的方法。
