CISPLATIN KINETICS

顺铂化学的实验和理论研究 (DDP)一直在继续，目标是描述 药物的体外反应动力学。主要活性物种 在药物的最初24小时内，已经确定了药物的途径 在各种缓冲无机溶液和等离子体中的反应 超滤液。DDP在缓冲液中的水解产物 氯化物溶液已经被测量了25个小时 PH在5.5范围内的高效液相色谱/电化学检测技术 到7.8。已经开发出了一个精确的动力学模型 解释了两种母体药物的浓度-时间分布 和一水/一羟基衍生物。此外，该比率 描述反单水到母体DDP反应的常数具有 并测定了其酸解离常数。 单水/单羟基物种。从这个模型外推到 血浆超滤液中的pH和氯化物水平显示 虽然血浆的相对碱性pH值(7.4)解释了 在观察到的药物反应性中，只有pH值是中等比例的 并不能解释所有的反应。因此氨基酸和克雷布斯循环 通常在血浆中发现的代谢物已经被研究 反应性。组氨酸、蛋氨酸和几个Krebs循环 代谢物被发现只是弱活性或非活性。 研究发现半胱氨酸的活性更强，但定量更准确。 需要进一步修改高效液相分离/检测 半胱氨酸/药物制品用一水溶液洗脱的方法 衍生品。

Experimental and theoretical studies on the chemistry of cisplatin (DDP) have been continued with the goal of characterizing the reaction kinetics of the drug in vitro. Principal reactive species and pathways have been identified over the first 24 hours of drug reaction in various buffered inorganic solutions and plasma ultrafiltrates. The hydrolysis products of DDP in buffered choloride solutions have been measured for 25 hours by HPLC/electrochemical detection techniques over a pH range of 5.5 to 7.8. A kinetic model has been developed that accurately accounts for the concentration-time profiles of both parent drug and monoaquo/monohydroxo derivatives. Furthermore, the rate constant describing the reverse monoaquo to parent DDP reaction has been determined as well as the acid dissociation constant of the monoaquo/monohydroxo species. Extrapolations from this model to the pH and chloride levels found in plasma ultrafiltrate reveal that, while the relatively alkaline pH of plasma (7.4) accounts for a moderate fraction of the observed drug reactivity, pH alone does not account for all reactivity. Hence amino acid and Krebs cycle metabolites normally found in plasma have been investigated for reactivity. Histidine, methionine, and several Krebs cycle metabolites were found to be only weakly reactive or unreactive. Cysteine was found to be more reactive but exact quantitation requires further modification of the HPLC separation/detection method since cysteine/drug products coelute with monoaquo derivatives.