Coloma F, Lacarelle B, Poitou P, Filleul A, Covo J, Catalin J
Laboratoire de toxicocinétique et pharmacocinétique EA 859, faculté de pharmacie, Marseille, France.
Bull Cancer. 1994 May;81(5):425-30.
We have examined the effect of cyclosporin A on transport processes (uptake, efflux, binding) of mitoxantrone in isolated rat liver cells. Accumulation and binding of mitoxantrone was rapid with or without cyclosporin A. The initial uptake was linear over a wide concentration range (1 to 1000 microM). For the first 100 s, the rate of uptake is constant. The uptake clearance ranged from 12.53 +/- 3.9 to 33.77 +/- 15.1 nl.min-cell-1 for different extracellular concentrations of mitoxantrone. Also cyclosporin A did not modified this coefficient. Initial binding of mitoxantrone to cell plasma membrane was estimated and it was modified by different extracellular concentrations of mitoxantrone but not by cyclosporin A. Respectively at 60 seconds it accounted to 79.6% and 81.6% of the total transport. Influx of mitoxantrone was not temperature sensitive. We next examined the efflux of mitoxantrone from cells that were preloaded with drug. Initial efflux was rapid for the first 5 minutes. Cyclosporin A slightly decrease this efflux (7%). The data suggest that the mechanism of uptake of mitoxantrone is passive diffusion and that cyclosporin A a p-glycoprotein 170 inhibitor agent has only a weak effect on efflux.
我们研究了环孢素A对米托蒽醌在离体大鼠肝细胞中的转运过程（摄取、外排、结合）的影响。无论有无环孢素A，米托蒽醌的蓄积和结合都很快。在很宽的浓度范围（1至1000微摩尔）内，初始摄取呈线性。在前100秒，摄取速率是恒定的。对于不同细胞外浓度的米托蒽醌，摄取清除率范围为12.53±3.9至33.77±15.1纳升·分钟·细胞-1。环孢素A也未改变该系数。估计了米托蒽醌与细胞质膜的初始结合，它受不同细胞外浓度的米托蒽醌影响，但不受环孢素A影响。分别在60秒时，它占总转运的79.6%和81.6%。米托蒽醌的内流对温度不敏感。接下来我们研究了预先加载药物的细胞中米托蒽醌的外排。初始外排在最初5分钟内很快。环孢素A使这种外排略有降低（7%）。数据表明米托蒽醌的摄取机制是被动扩散，并且环孢素A作为一种P-糖蛋白170抑制剂对外排只有微弱影响。
