Dedrick R L, Flessner M F
Biomedical Engineering and Instrumentation Program, National Center for Research Resources, National Institutes of Health, Bethesda, MD 20892, USA.
J Natl Cancer Inst. 1997 Apr 2;89(7):480-7. doi: 10.1093/jnci/89.7.480.
Both theory and clinical studies demonstrate that drug concentrations in the peritoneal cavity can greatly exceed concentrations in the plasma following intraperitoneal administration. This regional advantage has been associated with clinical activity, including surgically documented complete responses in ovarian cancer patients with persistent or recurrent disease following systemic therapy, and has produced a survival advantage in a recent phase III trial. Two pharmacokinetic problems appear to limit the effectiveness of intraperitoneal therapy: poor tumor penetration by the drug and incomplete irrigation of serosal surfaces by the drug-containing solution. We have examined these problems in the context of a very simple, spatially distributed model. If D is the diffusivity of the drug in a tissue adjacent to the peritoneal cavity and k is the rate constant for removal of the drug from the tissue by capillary blood, the model predicts that (for slowly reacting drugs) the characteristic penetration distance is (D/k)1/2 and the apparent permeability of the surface of a peritoneal structure is (Dk)1/2. The permeability-area product used in classical pharmacokinetic calculations for the peritoneal cavity as a whole is the sum of the products of the tissue-specific permeabilities and the relevant superficial surface areas. Since the model is mechanistic, it provides insight into the expected effect of procedures such as pharmacologic manipulation or physical mixing. We observe that large changes in tissue penetration may be difficult to achieve but that we have very little information on the transport characteristics within tumors in this setting or their response to vasoactive drugs. Enhanced mixing is likely to offer significant potential for improved therapy; however, procedures easily applicable to the clinical setting have not been adequately investigated and should be given high priority. Clinical studies indicate that an increase in irrigated area may be achieved in many patients by individualizing the dialysate volume and consideration of patient position.
理论和临床研究均表明，腹腔内给药后，腹腔内的药物浓度可大大超过血浆中的浓度。这种局部优势与临床活性相关，包括在系统治疗后患有持续性或复发性疾病的卵巢癌患者中经手术记录的完全缓解，并且在最近的一项III期试验中产生了生存优势。两个药代动力学问题似乎限制了腹腔内治疗的有效性：药物对肿瘤的穿透性差以及含药溶液对浆膜表面的冲洗不完全。我们在一个非常简单的空间分布模型的背景下研究了这些问题。如果D是药物在与腹腔相邻组织中的扩散系数，k是药物通过毛细血管血液从组织中清除的速率常数，则该模型预测（对于反应缓慢的药物）特征穿透距离为（D/k）1/2，腹膜结构表面的表观渗透率为（Dk）1/2。在经典药代动力学计算中用于整个腹腔的通透面积乘积是组织特异性渗透率与相关表面积乘积的总和。由于该模型是基于机制的，因此它可以深入了解诸如药理操作或物理混合等程序的预期效果。我们观察到，可能难以实现组织穿透的大幅变化，但在此情况下，我们对肿瘤内的转运特性或它们对血管活性药物的反应了解甚少。增强混合可能为改善治疗提供巨大潜力；然而，易于应用于临床环境的程序尚未得到充分研究，应给予高度优先考虑。临床研究表明，通过个体化透析液体积并考虑患者体位，许多患者可以实现冲洗面积的增加。
