Sadzuka Y, Nakai S, Miyagishima A, Nozawa Y, Hirota S
Lab. of Pharmaceutical Engineering, School of Pharmaceutical Sciences, University of Shizuoka, Japan.
J Drug Target. 1995;3(1):31-7. doi: 10.3109/10611869509015930.
The distribution of adriamycin (ADR) at a clinically relevant low dose of 2.5 mg/kg was compared to the distribution at a high dose of 7.5 mg/kg (dose often employed in distribution studies). ADR solution (ADRsol), plain liposomal ADR (PLADR) and polyethyleneglycol (PEG)-coated liposomal ADR (PEG-LADR) were injected into the tail vein of Wistar rats. The retention in serum was PEG-LADR > PLADR > ADRsol at both doses. In the high-dose study, ADR concentration in the liver and spleen at 4 h after administrations of PLADR and PEG-LADR were higher than that with ADRsol. On the other hand, in the low-dose study, reticuloendothelial system (RES) uptake of ADR was reduced by liposome encapsulation (liposomalization). Reduced ADR concentrations in the heart due to liposomalization were found only at the low doses. These results indicate that the difference in doses led to different distributions and that there is an optimal dose at which liposomes exhibit their objective distribution. A comparison of the ADR concentration in the spleen to that in the liver indicated RES saturation by increasing doses and the optimal dose being lower than the dose that saturates RES. Thus, distribution of liposome-entrapped ADR must be investigated at doses as close to the clinical dose as possible.
将阿霉素（ADR）在临床相关低剂量2.5mg/kg时的分布与高剂量7.5mg/kg（分布研究中常用剂量）时的分布进行了比较。将阿霉素溶液（ADRsol）、普通脂质体阿霉素（PLADR）和聚乙二醇（PEG）包被的脂质体阿霉素（PEG-LADR）注入Wistar大鼠的尾静脉。在两种剂量下，血清中的保留率均为PEG-LADR＞PLADR＞ADRsol。在高剂量研究中，给予PLADR和PEG-LADR后4小时，肝脏和脾脏中的阿霉素浓度高于ADRsol。另一方面，在低剂量研究中，脂质体包封（脂质体化）降低了网状内皮系统（RES）对阿霉素的摄取。仅在低剂量时发现脂质体化导致心脏中阿霉素浓度降低。这些结果表明，剂量差异导致了不同的分布，并且存在一个最佳剂量，在该剂量下脂质体呈现其目标分布。脾脏与肝脏中阿霉素浓度的比较表明，随着剂量增加RES会饱和，且最佳剂量低于使RES饱和的剂量。因此，必须在尽可能接近临床剂量的情况下研究脂质体包裹的阿霉素的分布。
