Alberts D S, Chen H G, Benz D, Mason N L
Br J Cancer. 1981 Mar;43(3):330-4. doi: 10.1038/bjc.1981.52.
The effect of renal failure on melphalan pharmacology and toxicity has been poorly understood. Such information is of interest because melphalan is the most commonly used anticancer drug in the treatment of multiple myeloma, which is frequently associated with renal failure. We have studied the disposition and marrow toxicity of parenteral melphalan in dogs before and after induction of renal failure with subtotal nephrectomy. The surgical procedure decreased the creatinine clearance by an average of 62% (P = 0.001). The lowest neutrophil counts following i.v. melphalan (1 mg/kg) averaged 4.9 x 10(3)/mm3 pre-nephrectomy and 0.9 x 10(3)/mm3 post-nephrectomy, respectively (P = 0.002). The mean lowest recorded platelet counts after melphalan (1 mg/kg) were 115 x 10(3)/mm3 in the pre-nephrectomized dogs, and 9.7 x 10(3/mm3 in those who had been nephrectomized (P = 0.002). Following nephrectomy, i.v. melphalan's terminal-phase plasma half-life and renal clearance were both raised (P = 0.02) to 75% over pre-nephrectomy values. These studies show that i.v. melphalan-induced myelosuppression is markedly increased and its plasma elimination and renal clearance significantly decreased in the presence of renal dysfunction in dogs. These data suggest that parenteral melphalan's starting dose be decreased by at least 50% when used in myeloma patients with renal failure.
肾衰竭对美法仑药理学及毒性的影响一直未得到充分了解。这类信息之所以引人关注，是因为美法仑是治疗多发性骨髓瘤最常用的抗癌药物，而多发性骨髓瘤常与肾衰竭相关。我们研究了在犬类中通过次全肾切除诱导肾衰竭前后，静脉注射美法仑的处置情况及骨髓毒性。手术操作使肌酐清除率平均降低了62%（P = 0.001）。静脉注射美法仑（1 mg/kg）后，最低中性粒细胞计数在肾切除术前平均为4.9×10³/mm³，肾切除术后平均为0.9×10³/mm³（P = 0.002）。美法仑（1 mg/kg）注射后，术前肾切除犬的平均最低记录血小板计数为115×10³/mm³，肾切除后的犬为9.7×10³/mm³（P = 0.002）。肾切除后，静脉注射美法仑的终末相血浆半衰期和肾清除率均升高（P = 0.02），比肾切除术前的值高出75%。这些研究表明，在犬类存在肾功能不全时，静脉注射美法仑引起的骨髓抑制明显增强，其血浆消除和肾清除率显著降低。这些数据表明，在肾衰竭的骨髓瘤患者中使用静脉注射美法仑时，起始剂量应至少降低50%。
