Hepburn T W, Davis C B, Urbanski J J, Smith B R, Schaefer W H, Carbonaro M A, Bugelski P J
Department of Toxicology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406, USA.
Drug Metab Dispos. 1995 Oct;23(10):1044-50.
Recombinant soluble CD4 (sT4; mol. wt. 45,000) has been studied extensively in Sprague-Dawley rats, and substantial renal processing has been indicated. In rats and monkeys, renal filtration and precipitation of sT4 in the distal nephron caused tubular cast nephropathy. Intravenous pharmacokinetics in the rat demonstrated that sT4 plasma clearance exceeded the glomerular filtration rate. In an effort to determine quantitatively the extent to which kidney and other tissues were responsible for sT4 catabolism, sT4 was labeled with trace amounts of dilactitol-[125I]tyramine and administered intravenously to Sprague-Dawley rats (1 mg/kg). Dilactitol-tyramine accumulates in lysosomes at the site of protein degradation. It has been used primarily to demonstrate hepatic catabolism of endogenous proteins. Blood samples were drawn for pharmacokinetic analysis, and selected tissues were removed to assess radiolabel distribution. Comparison of pharmacokinetic parameters derived from total plasma radiolabel and functional ELISA were not significantly different. Thus, covalent modification of sT4 with dilactitol-tyramine did not appreciably change the rate of clearance. From 3 to 24 hr after intravenous administration, 81.5 +/- 0.1% of the total administered radioactivity was found in the kidney. Approximately 8-13% of the administered dose was recovered in the liver. Macroscopic autoradiography of the kidney demonstrated accumulation of radiolabel in the cortex. Light microscopic autoradiography of the kidney following intravenous administration of directly radioiodinated sT4 confirmed cortical processing, because radiolabel was located primarily in epithelial cells of P1 and P2 segments of the proximal tubule after low intravenous doses (0.4-4 mg/kg). At 40 mg/kg, distal tubules and cortical collecting ducts were labeled as well. Thus, sT4 was filtered by the glomerulus, reabsorbed in the proximal tubule, and degraded in the lysosomal compartment.
重组可溶性CD4（sT4；分子量45,000）已在斯普拉格-道利大鼠中进行了广泛研究，并已表明存在显著的肾脏处理过程。在大鼠和猴子中，远端肾单位中sT4的肾脏滤过和沉淀导致肾小管铸型肾病。大鼠的静脉药代动力学表明，sT4的血浆清除率超过肾小球滤过率。为了定量确定肾脏和其他组织对sT4分解代谢的责任程度，用微量二乳糖醇-[125I]酪胺标记sT4，并静脉注射给斯普拉格-道利大鼠（1mg/kg）。二乳糖醇-酪胺在蛋白质降解部位的溶酶体中积累。它主要用于证明内源性蛋白质的肝脏分解代谢。采集血样进行药代动力学分析，并取出选定的组织以评估放射性标记分布。从总血浆放射性标记和功能性ELISA得出的药代动力学参数比较无显著差异。因此，用二乳糖醇-酪胺对sT4进行共价修饰并未明显改变清除率。静脉给药后3至24小时，肾脏中发现了81.5±0.1%的总给药放射性。在肝脏中回收了约8-13%的给药剂量。肾脏的宏观放射自显影显示放射性标记在皮质中积累。静脉注射直接放射性碘化sT4后肾脏的光镜放射自显影证实了皮质处理过程，因为在低静脉剂量（0.4-4mg/kg）后，放射性标记主要位于近端小管P1和P2段的上皮细胞中。在40mg/kg时，远端小管和皮质集合管也被标记。因此，sT4被肾小球滤过，在近端小管中重吸收，并在溶酶体区室中降解。
