Caffeic acid 靜脈連續輸注至家兔體後之 Glucuronidation 與
Sulfation 代謝變化
Glucuronidation and Sulfation of Caffeic acid in Rabbits after
Intravenous Infusion Administration
中文摘要
Caffeic acid (CA)為一天然的多酚類化合物。有關它在靜脈注
射 (Intravenous bolus administration) 與口服投與 (Oral
administration) 方面的藥物動力學研究已有學者提出報告。但是
以 Caffeic acid 進行靜脈連續輸注 (Intravenous infusion) 之藥物動
力學研究，尚未有研究報告發表。本實驗之研究目的，即是以靜
脈連續輸注之投與方式，投與 Caffeic acid 至家兔體內，來觀察其
藥物動力學之變化。
本實驗之研究方法是將 CA 以靜脈連續輸注與至家兔體內，使
其血中分別達到 5、15、30、60、120、180 微克/毫升之穩定
濃度，並收集其血液及尿液，利用高效液相層析法，檢測血漿及
尿中 CA 原態之濃度，之後利用藥動學專用程式 PCNONLIN 解析
CA 在家兔體內之動態；此外，亦將尿液以酵素進行水解，利用高
效液相層析法，間接檢測尿中 CA 結合態代謝物之濃度，以解析
CA 之代謝方式。
CA 靜脈連續輸注實驗結果顯示，(I)由靜脈輸注之藥物動力學
參數而推得的靜脈連續輸注速率(Infusion rate)，確實使血中分別
達到 5、15、30、60、120、180 微克/毫升之穩定濃度；當靜
脈連續輸注停止後，(1)排除半衰期會隨著 CA 穩定血中濃度的增
加，有漸漸延長的趨勢(Elimination half-life=14.80±0.72、17.73
±0.57、16.84±0.54、17.49±0.51、18.06±1.24 分鐘，
p<0.05)；(2)總清除率則為 17.45±0.47、18.63±0.30、17.79
±0.86、18.40±0.77、19.07±0.47 毫升/分鐘/公斤 (p<0.05)，
此排除半衰期的延長與總清除率的變化可能是高劑量 CA 靜脈連
續輸注使尿液酸化造成 CA 腎排泄再吸收與 CA 生體代謝變化之綜
合結果。(II)由家兔尿液結果，顯示隨著劑量的改變，CA 原態
(CA-F)、Caffeic acid 之 Sulfate 結合態(CA-S)與 CA 之 Glucuronide
結合態(CA-G)之間有著一定關係的消長，即(1)當穩定血中濃度由
5 微克/毫升增加至 30 微克/毫升時，CA-F 由 57.58%減少至
52.80% (p<0.05)、CA-S 由 2.08%增加至 6.64% (p<0.05)而 CA-G
由 0.77%增加至 4.06% (p<0.05)；(2)但是當穩定血中濃度由 30 微
克/毫升增加至 60 微克/毫升時，CA-F 由 52.80%略減少至
51.22%、CA-S 由 6.64%減少至 5.00% (p<0.05)，但 CA-G 由 4.06%
增加至 5.46% (p<0.05)；(3)至於當穩定血中濃度由 60 微克/毫升增
加至 120 微克/毫升、180 微克/毫升時，CA-F 由 51.22%減少至
50.70 再增加至 56.49% (p<0.05)、CA-S 由 5.00%減少至 1.98%
(p<0.05)，但 CA-G 卻先由 5.46%增加至 8.76%再減少至 5.77%
(p<0.05) ；其原因可能是在較低血中濃度時，大部分 CA 是進行
Sulfation 代謝反應，而在較高血中濃度時，大部分 CA 則是進行
Glucuronidation 代謝反應，至於在血中達到 180 微克/毫升穩定濃
度時，可能是兩種酵素均被飽和了。此一現象顯示 CA 之 Sulfation
代謝反應具有高親和力(High affinity)與低飽和力(Low capacity)之
特性，而 Glucuronidation 代謝反應則具有低親和力與高飽和力之
特性。
英文摘要
Caffeic acid (CA) is a natural phenolic compound. Its
pharmacokinetic behaviors have been studied in rabbits with
intravenous bolus and oral administration. However, literatures about the pharmacokinetic behaviors of CA in rabbits with intravenous infusion are scarce. The purpose of this study is the pharmacokinetic behaviors of CA in rabbit''s urine after intravenous infusion administration.
During the study, the concentration of CA in rabbits'' plasma are maintained at the steady-state concentrations (5、15、30、60、
120、180mg/ml) by infusing CA, then collecting the rabbits'' plasma and urine. The CA concentration in plasma and urine were detected by
high performance liquid chromatographer (HPLC). The PCNONLIN program is used to treat the pharmacokinetic parameters of CA from plasma. Furthermore, the enzymes (β-glucuronidase and sulftase)
were used to hydrolyze the CA conjugate metabolites in the rabbits'' urine.
The results of infusion of CA showed that (I) the infusion rates which is predicted from the intravenous pharmacokinetic parameters nearly made the rabbits'' plasma to reach the steady-state concentrations (5、15、30、60、120、180mg/ml). After stop the infusion, (1) the increase of CA Css prolongs Elimination half-life gradually (Elimination half-life =14.80±0.72、17.73±0.57、 16.84±0.54、17.49±0.51、18.06±1.24min, p<0.05)；(2) and
CLTotal data are 17.45±0.47、18.63±0.30、17.79±0.86、18.40 ±0.77、19.07±0.47ml/min/kg (p<0.05). These prolonging
Elimination half-life and the change of CLTotal mightbe caused by the CA reabsorption in acidic urine after high dose of CA infusion and the biotransformation of CA. (II) Comparison the predominance of free form and conjugated form of CA in rabbits, the change of free form (CA-F), sulfates (CA-S) and glucuronides (CA-G) has a dose-
dependent relationship. (1) When the Css increased from 5mg/ml to 30mg/ml, CA-F decreased from 57.58% to 52.80% (p<0.05)、CA-S increased from 2.08% to 6.64% (p<0.05) and CA-G increased from 0.77% to 4.06% (p<0.05). (2) But CA-F slightly decreased from 52.80% to 51.22%、CA-S decreased from 6.64% to 5.00% (p<0.05) and CA-G increased from 4.06% to 5.46% (p<0.05) when the Css increased from 30mg/ml to 60mg/ml. (3) Ferthermore when the Css increased from 60mg/ml to 180mg/ml, CA-F decreased from 53.36% to 50.70% then increased to 56.49% (p<0.05)、CA-S increased from 5.00% to 1.98% (p<0.05) and CA-G increased first from 5.46% to 8.76% then decreased to 5.77% (p<0.05). The results show that CA conjugation prefer sulfation when the low Css, and the major
conjugation of CA is glucuronidation in the high Css. When the Css reached 180mg/ml, sulfation and glucuronidation will be saturated. These phenomena indicate that sulfation of CA shows high affinity and low capacity, but glucuronidation of CA has low affinity and high capacity.
