Zima T, Jirsa M, Jirsa M, Bradová V, Stejskal J, Zabka J, Povýsil C, Janebová M
First Institute of Medical Chemistry and Biochemistry, Charles University, Prague, Czech Republic.
Physiol Res. 1997;46(5):351-5.
Photodynamic therapy (PDT) is now being used more frequently in carefully selected cases of malignancies. The drugs used for PDT are mostly derivatives of haematoporphyrine (HPD) and its active component photofrine II. Another compound prepared by total synthesis is meso-tetra-(4-sulfonatophenyl)-porphine (TPPS4) but its application in human medicine was rejected because of its neurotoxicity. Our TPPS4 was prepared by the method of Busby et al. in the modification of Jirsa and Kakac (1987). This product is purer and without neurotoxic effects. In this study, we concentrated our attention on the effect of TPPS4 on nephrotoxicity and its accumulation in some organs. As the parameters of toxic kidney damage we used urine levels of N-acetyl-beta-D-glucosaminidase (NAG), serum creatinine levels, glomerular filtration rate (GFR) and proteinuria. TPPS4 was administered i.v. in a dose of 25 mg/kg b.w. The animals were observed for 21 days after drug application. Urine and blood samples were collected over 24-hour periods on days 0, 5 and 21. The serum creatinine level was significantly higher only on day 5 (65.0+/-1.46 micromol/l vs 56.5+/-2.69 micromol/l on day 0, p<0.05). There were no significant changes in GFR, proteinuria or NAG activity in the urine during the experiment. AST serum activity was increased. We determined the concentration of TPPS4 (pmol/mg w.w.) in rat organs on the 21st day after the injection. The concentration of TPPS4 was high in kidneys (30.8+/-5.5), liver (13.5+/-2.0), lungs (11.7+/-4.6) and spleen (9.7+/-1.5), while the concentration in heart and brain was low. We conclude that TPPS4 has the highest concentration in the kidney 21 days after its administration and does not exert any nephrotoxic effects during this period.
光动力疗法（PDT）如今在经过精心挑选的恶性肿瘤病例中使用得越来越频繁。用于PDT的药物大多是血卟啉（HPD）及其活性成分光敏素II的衍生物。另一种通过全合成制备的化合物是中-四-（4-磺基苯基）-卟啉（TPPS4），但由于其神经毒性，它在人类医学中的应用被否决。我们的TPPS4是按照Busby等人的方法，并根据Jirsa和Kakac（1987年）的改进方法制备的。该产品纯度更高且无神经毒性作用。在本研究中，我们将注意力集中在TPPS4对肾毒性的影响及其在某些器官中的蓄积情况。作为肾脏毒性损伤的参数，我们采用了尿中N-乙酰-β-D-氨基葡萄糖苷酶（NAG）水平、血清肌酐水平、肾小球滤过率（GFR）和蛋白尿。TPPS4以25mg/kg体重的剂量静脉注射。给药后对动物观察21天。在第0、5和21天的24小时内采集尿液和血液样本。仅在第5天时血清肌酐水平显著升高（65.0±1.46微摩尔/升，而第0天时为56.5±2.69微摩尔/升，p<0.05）。实验期间，GFR、蛋白尿或尿中NAG活性均无显著变化。血清AST活性升高。我们在注射后第21天测定了大鼠器官中TPPS4的浓度（皮摩尔/毫克湿重）。TPPS4在肾脏（30.8±5.5）、肝脏（13.5±2.0）、肺脏（11.7±4.6）和脾脏（9.7±1.5）中的浓度较高，而在心脏和大脑中的浓度较低。我们得出结论，TPPS4给药21天后在肾脏中的浓度最高，且在此期间未产生任何肾毒性作用。
