二、Indican 於大鼠體內對 methotrexate 動力學之影響
本實驗室先前的研究結果顯示，許多富含多酚之中藥如大 黃、黃芩及葛根等與MTX 併服時，導致部分大鼠死亡（Chao et al., 2002），因此本實驗採平行設計給藥。單服 MTX 與併服三種劑量的 indican 後，血清中 MTX 之濃度及血藥經時變化圖如 Table 18 及 Fig 15 所示。單服 MTX 之平均血藥面積為 75.5 ± 24.2 μmol⋅min⋅L-1，平
均滯留時間為338.5 ± 168.0 min；併服 10 mg/kg indican 之平均血藥面 積為145.0 ± 6.9 μmol⋅min⋅L-1，平均滯留時間為 1033.7 ± 41.2 min。併 服20 mg/kg indican 之平均血藥面積為 201.3 ± 22.7 μmol⋅min⋅L-1，平 均滯留時間為1035.3 ± 43.7 min。併服 40 mg/kg indican 之平均血藥面 積為228.2 ± 35.2 μmol⋅min⋅L-1，平均滯留時間為958.9 ± 83.5 min。比 較四組結果，顯示併服10、20 及 40 mg/kg indican 時，平均血藥面 積分別增加了92 % （p = 0.20）、166 % ( p < 0.01 ) 及 202 % ( p <
0.01 )；平均滯留時間分別增加了 205 % ( p < 0.001 )、205 % ( p <
0.001 ) 及 183 % ( p < 0.01 )，如 Table 2-1 所示。
MTX 化學結構上之羧基於生理 pH 下會形成陰離子。許多研 究指出indoxyl sulfate 為 OATs 與 MRP 1、2、3 及 4 之受質（Deguchi et al., 2002）。MTX 也是 OATs 與 MRPs 之受質（Chen et al., Kruth et
al., 2001; Zeng et al., 2001）。另有研究指出，低濃度 MTX 的長時間 滯留比高濃度 MTX 的毒性更高，因為 MTX 與 MRPs 親合力低，
當MTX 以低濃度存在時，polyglutamyl synthase 與 MTX 之結合大 於 MRPs，而有利於 MTX-(Glu)n代謝物之產生。MTX-(Glu)n不是 MRPs 之受質，無法由細胞內外排，因此毒性頗強。因此 indoxyl sulfate 可能與 MTX 於體內會競爭 MRPs 或 OATs 等運送蛋白。當 indican 與 MTX 併用時，可能會因其代謝物 indoxyl sulfate 競爭 OATs 或 MRPs 而使 MTX 之排除減緩，導致 MTX 滯留於體內的時間延 長，造成代謝物MTX-(Glu)n增多，而毒性增強。
我們進一步比較不同劑量 indican 對 MTX 動力學的影響，20 mg/kg 及40 mg/kg indican 口服後對 MTX 血藥面積及滯留時間的增加程度 並無顯著差異。反觀indican 之動力學，20 mg/kg 與 40 mg/kg 兩劑 量的indoxyl sulfate 之 AUC 及 MRT 並無顯著差異。因此，20 mg/kg 與40 mg/kg indican 口服後，indoxyl sulfate 在體內與 MTX 競爭 MRPS
與/或 OAT 的程度應相仿。Indican 的非線性動力學行為，應可解釋 為何20 mg/kg 與 40 mg/kg 兩種劑量的 indican 對 MTX 動力學的 影響程度沒有明顯差異。
另外，我們由血藥經時變化圖及動力學參數亦可推論，代謝物 indoxyl sulfate 對 MTX 之排除有抑制的作用。
總之，indican 對 MTX 之血中動力學行為影響甚鉅，對於含有 indican 的板藍根或其他植物產品，建議避免與 MTX 以確保用藥安全。
三、Indoxyl sulfate 於大白鼠體內對 phenolsulphthalein 動力學之影響
本研究以大鼠為模型，引用 phenolsulphthalein (PSP)為
MRP2/OAT1,3 受質的模型分子，探討 MRP2/OAT1,3 對於 indoxyl sulfate 之排除所扮演的角色。本試驗以交叉設計給藥，單獨注射 PSP 及同時注射PSP 與 indoxyl sulfate 後，分析血清中 PSP 之濃度及血藥 經時變化，其結果如Table.22 及 Fig.16 所示。單獨投予 PSP 之平均 血藥面積為1271.8 ± 124.6 μg⋅min⋅mL-1，平均分佈體積為852.7 ± 180.1 mL；同時投予 indoxyl sulfate 時，PSP 之平均血藥面積為 4071.7
± 604.2 μg ⋅min ⋅mL-1，平均分佈體積為341.1 ± 51.5 mL。比較二組結
果顯示同時投予PSP 及 indoxyl sulfate 時，平均血藥面積顯著增加了 220 % ( p < 0.01)，而平均分佈體積顯著減少了 60 %（p＜0.05）。
近年研究指出 PSP 為 MRPs/OATs 之受質（Shirou, 2003）。無論 體內或體外試驗皆顯示，PSP 與 MRP2 及 OAT1,3 具有高親和力
（Shirou, 2003；Kari, 2005）。Indoxyl sulfate 在體內為 MRPs/OATs 的 受質，其中與OAT1,3 具有高親和力。OAT1 是位於近端腎小管的有 機陰離子運送蛋白，OAT3 則位於近端腎小管及遠端腎小管，PSP 對 OAT3 的親和力比 OAT1 高。因此當 indoxyl sulfate 與 PSP 併用時，
彼此競爭MRPs/OATs 而導致 PSP 之排除減緩，應可證明在 indoxyl
sulfate 的排除中，MRPs/OATs 扮演重要的角色。
Indoxyl sulfate 是一種內生性的腎毒性物質，並且會蓄積在慢 性腎病的大鼠及病人體內。本實驗結果顯示 indoxyl sulfate 對 PSP 可 能具抑制作用，表示它們有共同的運送蛋白。
結 論
1. 本研究建立了 HPLC-UV 分析法，能同時定量血清中 indican 及 indoxyl sulfate 濃度，可提供藥物動力學研究之參考。
2. 大鼠口服及靜脈注射 indican 後，indican 快速的代謝成 indoxyl sulfate，而主要以 indoxyl sulfate 存在於血液中，且滯留時間相當 長。透過口服兩種劑量的動力學研究顯示，indican 在大鼠體內表 現非線性動力學行為。
3. Indoxyl sulfate 在體內蓄積易加速腎功能損傷，對於含有 indican 的板藍根或其他植物產品，建議長期服用者應注意腎功能。
4. Indican 併服 MTX 時，顯著增加 MTX 的血薬面積及滯留時間。
對於吸收期之影響不明顯，而對排除有明顯的抑制作用。建議併 用含有 indican 的板藍根或其他相關植物產品時，應避免併服
MTX，以確保用藥安全。
5. 同時靜脈注射 PSP 與 indoxyl sulfate 時，indoxyl sulfate 抑制了 PSP 之排除，應可推論在 indoxyl sulfate 的排除中，MRP2 及 OAT1, 3 扮演重要之角色。
一、 Indican 於大鼠體內之代謝動力學
m
5 1 0 1 5 2 0 2 5 3 0 3 5 4 0 4 5 5 0
0 5 0 1 0 0
Fig.7 The chromatograms of indican (1), indoxyl sulfate (2) and methyl paraben (3): (a) serum sample after oral administration of indican. (b) Endogenous indoxyl sulfate.
mv
m i nu te s
0 2 0 4 0 6 0
0 2 0 4 0 6 0 8 0
(A) (B) (1)
(2) (3)
(1)
(2) (3)
Fig. 9 Mean (± S.E.) serum concentration-time profiles of indican (●) and
indoxylsulfate (○) after intravenous administration of indican (10.0 mg/kg) to six rats（n=6）.
Fig.10. Mean (± S.E.) serum concentration-time profiles of indican (●) and indoxyl sulfate (○) after oral administration of indican (20.0 mg/kg) to six rats
Fig.11 Mean (± S.E.) serum concentration-time profiles of indican (●) and indoxyl sulfate (○) after oral administration of indican (40.0 mg/kg) to six rats
Fig.12 Mean (±S.E.) serum concentration-time profiles of indican after oral administration of 20.0 mg/kg (●) and 40.0 mg/kg (○) of indican.
Fig.13 Mean (±S.E.) serum concentration-time profiles of indoxyl sulfate after oral administration of 20.0 mg/kg (●) and 40.0 mg/kg (○) of indican.
Time (min)
Fig.14 Mean (±S.E.) serum concentration-time profiles of endogenous indoxyl sulfate (●) in rats.
Table 6 Pharmacokinetic parameters of indican (ID) and indoxyl sulfate (IDS) of six rats after oral administration of 20.0 mg/kg and 40.0 mg/kg indican and
C max (nmol．mL-1): the peak or maximum concentration
AUC 0-4320 (nmol．min．mL-1): area under concentration-time curve to the last point MRT (min): mean residence time
Values are means ± SE. Means in a row without a common superscript differ. P < 0.05
Table 7 The regression equations, concentration ranges and correlation coefficients of indican and indoxyl sulfate in rat serum.
Constituents Conc. ranges (μg/mL) Regression equations r2 Indican 0.78 ~ 50.0 Y=0.60X-0.01 0.99
Indoxyl sulfate 0.63 ~ 20.0 Y=0.83X+0.08 0.99
Table 8. Recovery (%) of indican from rat serum (n=3).
Conc.
(μg/mL) 1 2 3 Mean±S.D.
25.0 98.0 90.9 95.0 94.6±3.5 6.3 97.4 102.5 100.3 100.1±2.6 1.6 91.3 99.4 98.1 96.3±4.3
Table 9. Recovery (%) of indoxyl sulfate from rat serum (n=3).
Conc.
(μg/mL) 1 2 3 Mean±S.D.
20.0 99.2 96.4 97.5 97.7±1.4 5.0 108.9 94.1 90.1 98.0±9.6 1.3 111.6 97.4 109.2 106.1±7.6
Table 10. Intra-day and inter-day analytical precision and accuracy of indican in rat serum.
Precision Accuracy
Intra-day Inter-day Intra-day Inter-day
Conc.
(μg/mL) Mean ± S.D. (C.V.%) Mean ± S.D. (C.V.%) Relative error (%) Relative error (%)
50.0 50.0 ± 0.2 0.4 50.0 ± 0.4 0.9 0.0 0.01
6.25 6.0 ± 0.2 3.7 6.2 ± 0.0 0.3 -4.7 -1.5
3.13 3.3 ± 0.1 2.2 3.2 ± 0.1 2.2 6.1 2.2
1.56 1.6 ± 0.1 9.3 1.6 ± 0.1 5.8 -0.07 2.3
0.78 0.9 ± 0.1 8.2 0.8 ± 0.0 5.4 10.1 -1.9
Table 11. Intra-day and inter-day analytical precision and accuracy of indoxyl sulfate in rat serum.
Precision Accuracy
Intra-day Inter-day Intra-day Inter-day
Conc.
(μg/mL) Mean ± S.D. (C.V.%) Mean ± S.D. (C.V.%) Relative error (%) Relative error (%)
20.0 20.2 ± 0.3 1.7 20.2 ± 0.1 0.5 0.9 1.0
10.0 9.7 ± 0.4 3.8 9.6 ± 0.7 6.9 -3.4 -4.1
5.0 4.9 ± 0.4 8.1 5.0 ± 0.0 0.6 -1.2 -1.0
1.3 1.4 ± 0.1 5.3 1.4 ± 0.2 10.8 10.8 11.4
0.6 0.7 ± 0.1 7.7 0.7 ± 0.1 7.3 14.9 18.0
Table 12 The serum concentrations ( nmol/mL ) of indican in six rats after oral administration of indican ( 20.0 mg/kg ).
Table 13. The serum concentrations ( nmol/mL ) of indoxyl sulfate in six rats after oral administration of indican ( 20.0 mg/kg ).
Table 14. The serum concentrations ( nmol/mL) of indican in six rats after intravenous administration of indican ( 10.0 mg/kg ).
Table 15 . The serum concentrations ( nmol/mL ) of indoxyl sulfate in six rats after intravenous administration of indican ( 10.0 mg/kg ).
Table16 The serum concentrations ( nmol/mL ) of indican in five rats after oral administration of indican ( 40.0 mg/kg ).
Table 17. The serum concentrations ( nmol/mL ) of indoxyl sulfate in six rats after oral administration of indican ( 40.0 mg/kg ).
Fig.15 Mean ( ±S.E. ) serum concentration-time profiles of MTX (a) after oral administration of MTX alone (5.0 mg/kg) (●), and coadministration with 10.0 mg/kg (○), 20.0 mg/kg (▼) and 40.0 mg/kg（▽） of indican ( A )；the semi-log
Table 18 Parmacokinetic parameters of methotrexate among rats after oral administration of methotrexatre alone ( 5.0 mg/kg ) and coadministration with 10.0 mg/kg, 20.0 mg/kg and 40.0 mg/kg of indican ( ID ).
Data expressed as mean±S.E
Vz/F: volume of distribution of the central compartment ( L ) CL/F: total body clearance ( L．min-1 )
Values are means ± SE. Means in a row without a common superscript differ. P < 0.05
Parameter MTX alone MTX MTX MTX
+ ID (10.0 mg/kg) + ID (20.0 mg/kg) + ID (40.0 mg/kg) n=7 n=6 n=6 n=5
Cmax (μmol．L-1) 0.27 ± 0.03 0.28±0.03 0.26±0.04 0.30±0.03 AUC 0-2880 75.5±24.2 a 145.0±6.90ab 201.3±22.7b 228.2±35.2b (μmol．min．L-1)
Vz/F (L) 19.6±3.5 37.3±4.7 36.1±6.36 28.3±2.07 CL/F (L．min-1) 0.06±0.0a 0.02±0.0b 0.01±0.0 b 0.02±0.0 b MRT (min) 338.5±168.0a 1033.7±41.2 b 1035.3±43.7 b 958.9±83.5 b
Table 19. The serum concentrations ( μmol/L ) of MTX in six rats after coadministration of MTX ( 5.0 mg/kg ) and 10.0 mg/kg indican.
Table 20. The serum concentrations ( μmol/L ) of MTX in six rats after coadministration of MTX ( 5.0 mg/kg ) and 20.0 mg/kg indican.
Table 21. The serum concentrations ( μmol/L ) of MTX in six rats after coadministration of MTX ( 5.0 mg/kg ) and 40.0 mg/kg indican.
Rats
Fig 16 Mean ( ±S.E. ) serum concentration-time profiles of PSP after intravenous administration of PSP alone ( 5.0 mg/kg ) (●) and coadministration with indoxyl sulfate 10.0 mg/kg (○) ( A )；the semi-log diagram ( B ).
Table 22. The regression equations, concentration ranges and correlation coefficients of PSP in rat serum.
Constituents Conc. ranges (μg/mL) Regression equations r2 PSP 0.39 ~ 12.5 Y=0.019X-0.00 0.9994
PSP 0.39 ~ 12.5 Y=0.019X+0.001 0.9994
Table 23. Comparison of pharmacokinetic parameters of PSP of six rats administered with intravenous PSP ( 5.0 mg/kg ) alone and with 10.0 mg/kg of indoxyl sulfate ( IS ).
Parameters PSP alone PSP＋IS (10.0 mg/kg) n=6 n=6
AUC 0-1440 1271.8±124.6 4071.7±604.2**
Vz 852.7±180.1 341.1±51.5*
MRT 397.1±51.3 572.2±21.9**
Half-life 1174.3±659.8 1916.9±1050.4 CL 1.1±0.3 0.3±0.1**
** p ＜ 0.01 compared with PSP alone.
Data expressed as mean±S.E
Table 25. The serum concentrations ( μg/mL ) of PSP in six rats after oral administration of PSP ( 5.0 mg/kg ) with buffer ( pH= 7.4 ).
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