含柚皮苷中藥之代謝動力學及其與西藥之交互作用;Metabolic pharmacokinetics of naringin-containing herbs and their interactions with drugs

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題名:	含柚皮苷中藥之代謝動力學及其與西藥之交互作用;Metabolic pharmacokinetics of naringin-containing herbs and their interactions with drugs
作者:	王孟珠;Meng-Ju Wang
貢獻者:	中國醫藥大學：中國藥學研究所博士班
關鍵詞:	柚皮苷;枳實;枳殼;化橘紅;動力學;交互作用;naringin;naringenin;pharmacokinetics;interactions;methotrexate;cyclosporine;tacrolimus;carbamazepine
日期:	2007-01-29
上傳時間:	2009-08-11 10:25:15 (UTC+8)
摘要:	柚皮苷(Naringin)為柑橘屬植物之主要黃酮成份。本研究以大白鼠探討柚皮苷及柚皮苷元(naringenin)之代謝動力學。柚皮苷元以靜脈注射與口服，而柚皮苷則口服單劑量與多劑量。另外，於多劑量口服柚皮苷達穩定狀態後，採集腦、心、肝、脾、腎等組織樣品，利用HPLC分析血清及組織中之柚皮苷及其代謝物。分析結果顯示給予柚皮苷元及柚皮苷後，於循環與組織中皆主要以柚皮苷元之結合態代謝物存在。另外分別口服單劑量枳實(UF)、枳殼(RP)及化橘紅(CGP)三種富含柚皮苷之中藥水煎劑，但血中無法偵測出柚皮苷及其代謝物。葡萄柚汁富含柚皮苷與柚皮苷元。本研究探討葡萄柚汁中柚皮苷及其結合態代謝物於人體內之尿藥動力學。受試者飲用葡萄柚汁後，分段收集24小時內之尿液。分析結果顯示，柚皮苷元以葡萄糖醛酸與硫酸結合態代謝物由尿中排出，而偵測不出柚皮苷及柚皮苷元。 MTX (Methotrexate) 為治療指數狹窄之免疫抑制劑及抗癌藥，於體內之運輸、排除與multidrug resistance proteins (MRPs)及organic anion transporter (OATs) 有關。柚皮苷口服後於體循環中以葡萄糖醛酸與硫酸代謝物存在，它們在生理pH環境下為陰離子，可能為MRPs與OATs之受質，故本研究探討柚皮苷及化橘紅對MTX動力學之影響。結果顯示併服單劑量、多劑量柚皮苷或化橘紅，皆使MTX之血藥面積及平均滯留時間顯著增加，甚至產生致死毒性。為了用藥安全，服用MTX之病患應避免與柚皮苷或富含柚皮苷之中藥製劑併服。 Cyclosporin與tacrolimus為治療指數極低之免疫抑制劑，臨床上發現葡萄柚汁顯著提高兩者的血中濃度。本研究以大白鼠探討併服枳實、枳殼與化橘紅三種柑橘屬中藥對cyclosporin與tacrolimus動力學之影響。結果顯示併服化橘紅對cyclosporin與tacrolimus血藥面積與血峰濃度皆顯著增加；然而併服枳實時卻顯著降低；併服枳殼則對兩者動力學無影響。建議服用cyclosporin與tacrolimus之移植病患應避免併服柑橘屬中藥，以確保療效與安全。 Carbamazepine (CBZ) 為臨床常用之抗癲癇藥，治療指數狹窄，文獻報導其體內之代謝、運輸、排除與CYPs、P-gp及MRP2有關。本研究以大白鼠探討柚皮苷與化橘紅對CBZ動力學之影響。利用HPLC定量血清中CBZ及其活性代謝物CBZ-10,11-epoxide。結果顯示，併服柚皮苷與化橘紅後，對CBZ及CBZ-10,11-epoxide之全身暴露均無顯著影響，僅柚皮苷對CBZ的血峰濃度明顯增高。 Naringin is a major flavonoid in citrus fruits. This study investigated the metabolic pharmacokinetics of naringin and naringenin in rats. Naringenin was administered to rats via intravenous bolus and oral route, whereas naringin was given orally as single dose and multiple doses. After multiple-dose administration of naringin, naringenin sulfates and glucuronides gradually accumulated in the circulation. Tissue samples including brain, heart, liver, spleen and kidney were collected after perfusion and analyzed by high performance liquid chromatography method. The results showed that the sulfates and glucuronides of naringenin were exclusively present in the circulation and tissue whether naringenin or naringin was given to rats. Neither parent forms of naringin and naringenin nor their conjugates were detected in serum when unripe fruits (UF), ripe peels (RP) of Citrus aurantium and peels of Citrus grandis (CGP) were given. Therefore, pharmacologists should focus more on the bioactivities of conjugated metabolites of naringenin. Grapefruit juice is rich in naringin and naringenin. Urine samples were collected from volunteers within 24 h after taking grapefruit juice. The results indicated that glucuronides and sulfates of naringenin were the major metabolites of naringin excreted in urine. Methotrexate (MTX) is an immunosupressant and anticancer agent with narrow therapeutic range. Multidrug resistance proteins (MRPs) and organic anion transporter (OATs) were reported to be associated with the transport of MTX in vivo. Judging from the finding that naringin was predominantly present as glucuronides and sulfates in the circulation, which exist as aniones under physiological pH and thus are probable substrates of MRPs and OATs, it is plausible to infer that coadministrations of naringin and CGP may lead to clinically relevant interaction with MTX. Rats were orally administered MTX without and with single dose as well as pretreatment with multiple doses of naringin and CGP, respectively. The results showed that AUC0-t and MRT of MTX were significantly increased by coadminstrations of single and multiple doses of naringin and CGP. More importantly, the multiple dose intake of naringin and CGP resulted in fatal interaction in rats. For the sake of drug safety, the concurrent use of naringin and CGP with MTX should be avoided. Cyclosporine and tacrolimus are potent immunosuppressive agents with narrow therapeutic range. They are subject to clinically relevant interaction with Citrus herb as with grapefruit juice. This study investigated the effects of coadministrations of UF, RP and CGP on the pharmacokinetics of cyclosporine and tacrolimus. The results showed that coadminstration with CGP significantly increased the AUC0-t and Cmax of cyclosporine and tacrolimus; however, coadministration with UF significantly decreased the AUC0-t and Cmax. When RP was coadministered, no conspicuous alteration of cyclosporine or tacrolimus pharmacokinetics were observed. We suggested that for the sake of safety, the concurrent use of Citrus herbs with cyclosporine and tacrolimus should be avoided. Carbamazepine (CBZ) is an anti-epileptic drugs with narrow therapeutic window. CYPs, P-gp and MRP2 were reported to be associated with the metabolism and transport of CBZ in vivo. This study investigated the effects of naringin and CGP on the pharmacokinetics of CBZ. The results showed that naringin and CGP exerted no conspicuous alteration on systemic exposure of CBZ and the active metabolite CBZ-10,11-epoxide. Only naringin significantly increased the Cmax of CBZ.
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