In vivo clearance predictions from in vitro assays require scaling factors to relate the concentrations of hepatocytes or microsomal protein to the intact liver. 2. The aims were to measure the variability in scaling factors for Wistar rat and beagle dog for which the literature is particularly scarce and determine any sex differences. 3. Scaling factors were determined by comparing the cytochrome P450 (P450) content in hepatocytes or microsomes against the P450 content of fresh liver homogenate. The use of fresh homogenate is recommended as freezing can increase contamination and affect the P450 assay. 4. Mean(geo) hepatic microsomal concentrations in Wistar rats were 61 mg g(-1) liver (95% confidence interval (CI); 47-75 mg g(-1) liver) and in beagle dogs 55 mg g(-1) liver (95% CI = 48-62 mg g(-1) liver). Mean(geo) hepatocellularity was 163 x 10(6) cells g(-1) liver for Wistar rats (95% CI = 127-199 x 10(6) cells g(-1) liver) and 169 x 10(6) cells g(-1) liver (95% CI = 131-207 x 10(6) cells g(-1) liver) for beagle dogs. The data generated in this study indicate a consistency in scaling factors between rat and dog. No sex differences were observed.
摘要
体外试验的体内清除率预测需要比例因子，以便将肝细胞或微粒体蛋白的浓度与完整肝脏相关联。2. 目的是测量文献中特别缺乏的Wistar大鼠和比格犬比例因子的变异性，并确定是否存在性别差异。3. 通过比较肝细胞或微粒体中的细胞色素P450（P450）含量与新鲜肝脏匀浆的P450含量来确定比例因子。建议使用新鲜匀浆，因为冷冻会增加污染并影响P450测定。4. Wistar大鼠肝脏微粒体的平均（几何）浓度为61 mg g(-1)肝脏（95%置信区间（CI）；47 - 75 mg g(-1)肝脏），比格犬为55 mg g(-1)肝脏（95% CI = 48 - 62 mg g(-1)肝脏）。Wistar大鼠的平均（几何）肝细胞数量为163×10(6)个细胞g(-1)肝脏（95% CI = 127 - 199×10(6)个细胞g(-1)肝脏），比格犬为169×10(6)个细胞g(-1)肝脏（95% CI = 131 - 207×10(6)个细胞g(-1)肝脏）。本研究产生的数据表明大鼠和犬之间比例因子具有一致性。未观察到性别差异。
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