Gibey R, Henry J C
Laboratoire de Biochimie Médicale, CHU Saint-Jacques, Besançon.
Pathol Biol (Paris). 1991 May;39(5):530-3.
Injection of diltiazem (40 mg/kg/d) to gentamicin (75 mg/kg/d = G 75 or 100 mg/kg/d = G 100) treated rats enhances aminoglycoside-induced nephrotoxicity. As a result of this combination, acute renal failure becomes systematic and is often irreversible. The lesion is of tubular origin and is characterized by a large increase in the urinary N-acetyl-beta-D-glucosaminidase (u-NAG) activity and its NAG-B isoenzyme level. The phenomenon is twice as marked with G 75 (u-NAG x 6.8, NAG-B x 2.2) as with G 100 (u-NAG x 3.1, NAG-B x 1.1). The effect seems to be attenuated if diltiazem is administered as a preventive treatment or in drinking water. As well as its diuretic properties, diltiazem may aggravate the renal toxicity of gentamicin by reducing the proximal tubular availability of calcium. Diltiazem inhibits reabsorption and behaves like a non-competitive inhibitor of calcium. This deficiency favours the proximal tubular binding and the non-specific penetration of gentamicin in the cytosol and cellular organelles (microsomes, mitochondria). The tubular toxic symptoms which ensure (inactivation of membranaceous enzyme, reduction of microsomal protein synthesis and ATP level, decreased of solute reabsorptive flux) lead in turn to proximal tubular necrosis and acute renal failure.
给接受庆大霉素（75mg/kg/天 = G75或100mg/kg/天 = G100）治疗的大鼠注射地尔硫䓬（40mg/kg/天）会增强氨基糖苷类药物诱导的肾毒性。由于这种联合作用，急性肾衰竭会全身性发作且往往不可逆转。该损伤起源于肾小管，其特征是尿N - 乙酰 - β - D - 氨基葡萄糖苷酶（u - NAG）活性及其NAG - B同工酶水平大幅升高。G75组（u - NAG升高6.8倍，NAG - B升高2.2倍）的这种现象比G100组（u - NAG升高3.1倍，NAG - B升高1.1倍）明显两倍。如果将地尔硫䓬作为预防性治疗药物给药或加入饮用水中，这种作用似乎会减弱。除了其利尿特性外，地尔硫䓬可能通过降低近端肾小管对钙的摄取来加重庆大霉素的肾毒性。地尔硫䓬抑制重吸收，表现为钙的非竞争性抑制剂。这种钙缺乏有利于庆大霉素在近端肾小管的结合以及在细胞质和细胞器（微粒体、线粒体）中的非特异性渗透。由此导致的肾小管毒性症状（膜性酶失活、微粒体蛋白质合成和ATP水平降低、溶质重吸收通量减少）进而导致近端肾小管坏死和急性肾衰竭。
