| 摘要: | 本計劃主要是研究賦型劑pluronicÒ對
藥品在肝膽運輸的影響。pluronicÒ為一系列
三區塊型(A-B-A)聚合物的總稱，是一類常
用於藥品製劑的非離子型賦型劑。近年來廣
用於各類製劑的開發，特別是使用在癌症與
愛滋病的藥劑開發與基因製劑的研究。因為
癌病與愛滋病用藥在體內的輸送會受到
MDR/MRP的影響，因而此類賦型劑是否影
響MDR/MRP 輸送子而對藥品輸送有所影
響的問題，在近來文獻中亦有所報導，但這
些文獻僅著重在小腸與腦膜的影響，至今並
無研究pluronicÒ對藥品在肝膽輸送的影響
報告。
本實驗室在執行前年國科會補助之研
究計畫時，卻發現一被文獻報導為對
MDR/MRP 輸送子微影響的pluronicÒ-X 賦
型劑對藥品ciprofloxacin的膽汁排除有顯著
的抑制。由此推論此類賦型劑不僅會改變藥
物在吸收與分佈的藥動性質，也會影響藥品
在膽汁的排除，甚至進而可能會影響藥品的
腎臟排除與出現在腸道的再吸收現象。此特
殊賦型劑如何影響藥品在肝膽輸送的機
轉，顯然值得進一步去探討研究，而能對此
賦型劑在製劑的臨床應用與限制有更進一
步的瞭解。
由於藥品在肝臟的輸送會受到OATPs,
MDRs and MRPs等輸送子的影響，典型受
質如： digoxin (Mdr1a/1b and Oatp2),
doxorubicin (Mdr1a/1b and Mrp2), pravastatin
(Oatp2), cisplatin (Mrp2), glyburide (Bsep)
and cyclosporin A (Mdr1a/1b)等預計將選用
為評估的探針藥品。
計劃中將以大鼠為研究之模式動物，在
藥物動力學臨床前試驗階段，為快速瞭解藥
品體內藥物動力學特性，大鼠為最常使用的
動物模式。在研究藥品代謝相關的交互作用
時，亦喜使用此動物模式。實驗分為老鼠體
內動力學試驗及原位離體肝臟灌流(Liver
perfusion)二部分。
本年度我們提出賦型劑對藥品肝膽輸
送的機轉研究，特別是針對從未報導過會抑
制體內ABC 輸送子的Pluronic-X 來研究，
我們相信此研究的成果，將有助於瞭解賦型
劑對藥品肝臟排除的機轉，有助於藥品製劑
在賦型劑上的選擇，對於現今國家生技重點
中草藥製劑開發也將有所助益。
This program is developed to evaluate
the impact of Pluronic –X on hepatobiliary
secretion of drugs. Pluronicâ block
copolymers, poloxamers, consist of ethylene
oxide (EO) and propylene oxide (PO) blocks
arranged in a traditional A-B-A structure. This
arrangement results in an amphiphilic nature,
in which the number of hydrophilic EO and
hydrophobic PO units can be altered. The use
of Pluronicâ-based formulations includes gels,
w/o and o/w emulsions, nanoparticles coated
2
by the block copolymer and solid polymer
blends. Recently, successful experiences on
using these polymers in drugs (i.e., anticancer
and antiviral agents) and gene delivery make
them attract more attentions. It has been
discovered that Pluronicâ polymers can inhibit
of Pgp and MRP1/MRP2 drug efflux system.
This Effect of Pluronicâ on drug metabolism
was only evaluated in MRP close related
GSH/GST detoxification system. However, all
these observation were based on studies on
cell-lines and have never been evaluated on
drug biliary secretion in other group.
Our previous studies demonstrated that a
specific hydrophilic Pluronic-X can decrease
biliary secretion of ciprofloxacin. This
phenomenon could be due to its inhibition
effect on Pgp or Mrp related efflux proteins. A
surprising finding is that this specific Pluronic
block copolymer (Pluronic-X) is hydrophilic. It
was suggested to be ineffective on the inhibion
of MDR/MRP transporters previously.
Apparently to us, it is worth to further
investigate the impact of excipients on drug
biliary secretion, especially to Pluronic-X.
The aim of the present study is to
investigate effects of Pluronicâ-X on its
possible role of hepatobiliary transporters,
selectively (Mdr1a/1b, Mdr2, Mrp2, Bsep, and
Oatps). We’ll use in situ isolated perfused rat
liver system to evaluate the inhibition effects of
Pluronic-X on specific substrates of the
investigated transporter. To evaluate the
impact of Pluronic-X on the specific substrate
of ABC drug efflux pumps and Oatps, the
following typical substrates: digoxin
(Mdr1a/1b and Oatp2), doxorubicin
(Mdr1a/1b and Mrp2), pravastatin (Oatp2),
cisplatin (Mrp2), glyburide (Bsep) and
cyclosporin A (Mdr1a/1b), will be chosen. In
vivo effects will be followed.
In terms of clinical/biopharmaceutical
benefits, the results of this program will be an
important new finding for hydrophilic Pluronic
block copolymers and will provide valuable
insights into whether Pluronic-X can affect
hepatobiliary secretion of drugs and which
transporters could be involved. It will be
helped in selecting excipients in drug
formulation. |
