Riviere J E, Page R L, Rogers R A, Chang S K, Dewhirst M W, Thrall D E
College of Veterinary Medicine, North Carolina State University, Raleigh 27606.
Cancer Res. 1990 Apr 1;50(7):2075-80.
The purpose of this study was to investigate the pharmacokinetics and tissue disposition of cisplatin (CDDP) in euthermic and hyperthermic dogs to determine if hyperthermic alteration of tissue CDDP concentration is uniform. Eighteen female beagle dogs received 20, 50, or 80 mg/m2 CDDP by constant infusion for 60 min under normothermic or hyperthermic conditions (n = 3/subgroup). Blood, plasma, and ultrafiltered plasma samples were collected during the infusion. At termination of infusion, animals were immediately sacrificed, all major tissues were collected, and platinum levels were determined by atomic absorption spectroscopy. Platinum concentrations in all blood fractions of hyperthermic dogs tended to be lower than those of normothermic dogs. The correlation between dose and blood area under the concentration-time curve was linear at both temperatures. Each tissue concentration was normalized for that individual dog's blood area under the curve. The ratio of relative extraction at 42 degrees C to that at 37 degrees C were compared for each tissue. Values of 1.0 were interpreted as indicating uniform relative tissue extraction at each temperature. Values of greater than 2.0 were obtained in lung and ileum, while values of greater than 1.5 were obtained in liver, adrenal, stomach, colon, duodenum, spleen, and pancreas. Values of less than 1.0 were obtained in skin and superficial lymph nodes. These results indicate that hyperthermia significantly alters the pattern of CDDP tissue disposition in a nonuniform manner and that pharmacokinetic data obtained at one temperature, e.g., areas under the curve, cannot be used to directly predict tissue concentrations at another temperature.
本研究的目的是调查顺铂（CDDP）在体温正常和体温升高的犬体内的药代动力学及组织分布情况，以确定组织中CDDP浓度的高温改变是否一致。18只雌性比格犬在常温或高温条件下（每组n = 3），通过持续输注60分钟接受20、50或80mg/m²的CDDP。输注过程中采集血液、血浆和超滤血浆样本。输注结束时，立即处死动物，收集所有主要组织，并通过原子吸收光谱法测定铂含量。体温升高的犬所有血液组分中的铂浓度往往低于体温正常的犬。在两个温度下，剂量与浓度-时间曲线下的血药面积之间的相关性均呈线性。将每只犬的每个组织浓度按照该犬的曲线下血药面积进行标准化。比较了每个组织在42℃和37℃时的相对摄取率。将1.0的值解释为表明在每个温度下组织相对摄取均匀。肺和回肠的相对摄取率大于2.0，而肝、肾上腺、胃、结肠、十二指肠、脾和胰腺的相对摄取率大于1.5。皮肤和浅表淋巴结的相对摄取率小于1.0。这些结果表明，高温以非均匀方式显著改变了CDDP的组织分布模式，并且在一个温度下获得的药代动力学数据（例如曲线下面积）不能直接用于预测另一温度下的组织浓度。
