Makos J D, Malloy C R, Sherry A D
Department of Chemistry, University of Texas at Dallas, Richardson, 75083-0688, Texas, USA.
J Appl Physiol (1985). 1998 Nov;85(5):1800-5. doi: 10.1152/jappl.1998.85.5.1800.
The distribution of TmDOTP5- in rat tissue was compared with CoEDTA-, an anionic complex previously used as a marker of extracellular space. Heart, liver, muscle, blood, and urine were collected from rats after infusion of either complex and were quantitatively analyzed by atomic absorption spectroscopy. Although total TmDOTP5- in blood and tissue was consistently lower (0.88 +/- 0.04; n = 6) than CoEDTA- after an identical infusion protocol (presumably because of some association of the phosphonate complex with bone), a comparison of blood and tissue contents indicated that the two anionic complexes distributed into identical extracellular spaces. Relative extracellular space in the in vivo liver, as determined by TmDOTP5- and CoEDTA-, was 0.18 +/- 0.02 and 0.15 +/- 0.01, respectively. The corresponding relative extracellular space values for the in vivo heart reported by the two agents were identical (0. 11 +/- 0.02). Experiments were also performed to evaluate the washout kinetics of TmDOTP5- from anesthesized rats. In rats given a total dose of 0.16 mmol TmDOTP5-, 81% appeared in urine by 180 min, <2% was found in all remaining soft tissue, leaving approximately 18% undetected. The rate of Tm appearance in urine was fit to a standard pharmacokinetic model that included four tissue compartments: plasma, one fast equilbrating space, one slow equilibrating space, and one very slow equilibrating space (presumably bone). The best fit result suggests that the highly charged TmDOTP5- complex is cleared from plasma more rapidly than is the typical lower charged Gd-based contrast agents and that release from bone is slow compared with renal clearance.
将大鼠组织中TmDOTP5-的分布与CoEDTA-进行了比较，CoEDTA-是一种先前用作细胞外间隙标志物的阴离子络合物。在向大鼠输注这两种络合物中的任何一种后，收集心脏、肝脏、肌肉、血液和尿液，并通过原子吸收光谱法进行定量分析。尽管在相同的输注方案后，血液和组织中的总TmDOTP5-始终低于CoEDTA-（0.88±0.04；n = 6）（可能是因为膦酸酯络合物与骨有一定关联），但血液和组织含量的比较表明，这两种阴离子络合物分布在相同的细胞外间隙中。通过TmDOTP5-和CoEDTA-测定的体内肝脏相对细胞外间隙分别为0.18±0.02和0.15±0.01。两种试剂报告的体内心脏相应相对细胞外间隙值相同（0.11±0.02）。还进行了实验以评估TmDOTP5-在麻醉大鼠体内的清除动力学。在给予总剂量为0.16 mmol TmDOTP5-的大鼠中，到180分钟时，81%出现在尿液中，在所有其余软组织中发现的不到2%，约18%未检测到。尿液中Tm出现的速率符合一个标准药代动力学模型，该模型包括四个组织隔室：血浆、一个快速平衡空间、一个缓慢平衡空间和一个非常缓慢平衡空间（可能是骨）。最佳拟合结果表明，高电荷的TmDOTP5-络合物从血浆中清除的速度比典型的低电荷钆基造影剂更快，并且与肾脏清除相比，从骨中释放的速度较慢。
