抗壞血酸 (ascorbic acid) 為人體必須維生素之一，廣泛存在於蔬果中，也是一種民眾常用的膳食補充品，慢性病患服用抗壞血酸的情形相當普遍。因此抗壞血酸與其他藥物併用的利與弊值得關注。
Cyclosporine (CsA) 為免疫抑制劑，常用於器官移植或自體免疫疾病。Tamoxifen (TAM) 為雌激素拮抗劑，臨床上用於治療雌激素受體陽性之乳癌。已有研究報導此二藥物皆為藥物運輸蛋白 P-glycoprotein (P-gp) 與藥物代謝酵素 CYP 3A4 的受質，本研究以之作為 P-gp 與 CYP 3A4 之探針藥物，探討抗壞血酸對 P-gp 與 CYP 3A4 之影響。
本研究以大鼠為模型，控制組單獨口服 CsA 或 TAM，實驗組併服單劑量或多劑量抗壞血酸，給藥後於特定時間點採血，CsA 之血中濃度利用螢光偏極免疫法定量，而 TAM 及其代謝物以 LC-MS 分析。
結果顯示，併服單劑量抗壞血酸使 CsA 之 AUC 與 Cmax 分別降低了
79.5 % 及 72.4 %，併服多劑量抗壞血酸則使 CsA 之 AUC 與 Cmax 分別降低了 77.2 % 及 65.3 %。然而，併服單劑量抗壞血酸對 TAM 及其代謝物之動力學參數皆未造成顯著影響。進一步以體外實驗探討交互作用之機制，結果顯示抗壞血酸活化 P-gp 之外排功能，而對 CYP 3A4 之活性並無影響。
綜言之，抗壞血酸是 P-gp 之活化劑，但並非 CYP 3A4 之調控劑。
Ascorbic acid, one of the essential vitamins for human body, is widely distributed in many natural fruits and vegetables. It is a common dietary supplement that is not uncommon in chronic patients. Therefore, the benefits or risk of the combined use of ascorbic acid with medicines warrants investigation.
Cyclosporine (CsA) is an immunosuppressant clinically used to prevent rejection of allograft organ or for the treatment of autoimmune diseases. Tamoxifen (TAM) is an estrogen antagonist clinically used for the treatment of estrogen receptor positive breast cancer. Both CsA and TAM have been reported as substrates of P-glycoprotein (P-gp) and CYP 3A4. In this study, CsA and TAM were used as probe drugs to investigate the effect of ascorbic acid on P-gp and CYP 3A4.
Rats were administrated CsA or TAM alone and coadministrated with single or multiple doses of ascorbic acid. Blood samples were collected at predetermined time points. The blood concentrations of CsA were determined by fluorescence polarization immunoassay. TAM and its metabolites were analyzed by LC-MS method.
The results showed that coadministration with single dose of ascorbic acid significantly decreased the AUC and Cmax of CsA by 79.5 % and 72.4 %, and mutiple doses of ascorbic acid decreased the AUC and Cmax of CsA by 77.2 % and 65.3 % respectively. However, coadministration of ascorbic acid did not significantly alter the pharmacokinetics of TAM. Mechanism studies showed that ascorbic acid activated the efflux function of P-gp, but did not affect the activity of CYP 3A4.
In conclusion, ascorbic acid is an activator of P-gp, but not a modulator of CYP 3A4.
