Wang L H, Fielding R M, Smith P C, Guo L S
Division of Pharmacokinetics and Drug Metabolism, Burroughs Wellcome Co., Research Triangle Park, NC 27709, USA.
Pharm Res. 1995 Feb;12(2):275-83. doi: 10.1023/a:1016243313027.
The pharmacokinetic profiles of amphotericin B (AmB) after administration of Amphocil, an AmB/cholesteryl sulfate colloidal dispersion (ABCD) and the micellar AmB/deoxycholate (Fungizone) were compared after repeated dosing in rats. After administration of ABCD and Fungizone at an equal AmB dose (1 mg/kg), AmB concentrations in plasma and most tissues were lower for the ABCD dose, especially in the kidneys where reduced drug concentration correlated with reduced nephrotoxicity. In contrast, AmB concentrations in the liver were substantially higher when ABCD was administered; however, without an accompanying increase in hepatotoxicity. Daily administration of ABCD for 14 days did not lead to AmB accumulation in plasma; while a slight accumulation was observed after multiple administration of Fungizone. AmB was eliminated more slowly from the plasma and various tissues and urinary and fecal recoveries of AmB were reduced after ABCD administration. These results suggest that ABCD may be stored in tissues in a form that is less toxic and is eliminated from the systemic circulation by a different mechanism than the free and protein-bound AmB in plasma. AmB accumulation in the spleen was observed when higher, doses of ABCD (5 mg/kg) were administered, which could be due to saturation of hepatic uptake of AmB. Comparison of spleen concentrations of AmB between ABCD and Fungizone at 5 mg/kg AmB doses was not possible because of Fungizone's toxicity in rats. In all other organs, AmB concentrations reached or approached a steady state within two weeks of dosing with ABCD. Urinary and fecal clearences of AmB were not different between ABCD and Fungizone administration.(ABSTRACT TRUNCATED AT 250 WORDS)
在大鼠重复给药后，比较了两性霉素B（AmB）/硫酸胆固醇胶体分散体（ABCD，商品名Amphocil）和胶束型两性霉素B/脱氧胆酸盐（商品名Fungizone）给药后两性霉素B（AmB）的药代动力学特征。以相等的AmB剂量（1mg/kg）给予ABCD和Fungizone后，ABCD剂量组血浆和大多数组织中的AmB浓度较低，尤其是在肾脏，药物浓度降低与肾毒性降低相关。相比之下，给予ABCD时肝脏中的AmB浓度显著更高；然而，肝毒性并未随之增加。连续14天每日给予ABCD未导致血浆中AmB蓄积；而多次给予Fungizone后观察到有轻微蓄积。给予ABCD后，AmB从血浆和各种组织中的消除更慢，尿液和粪便中AmB的回收率降低。这些结果表明，ABCD可能以毒性较小 的形式储存在组织中，并通过与血浆中游离和蛋白结合的AmB不同的机制从体循环中消除。给予较高剂量的ABCD（5mg/kg）时，观察到脾脏中有AmB蓄积，这可能是由于肝脏对AmB摄取饱和所致。由于Fungizone对大鼠有毒性，因此无法比较5mg/kg AmB剂量下ABCD和Fungizone之间脾脏中AmB的浓度。在所有其他器官中，给予ABCD两周内AmB浓度达到或接近稳态。给予ABCD和Fungizone后，AmB的尿液和粪便清除率没有差异。（摘要截断于250字）
