單羥黃酮、蒽醌、三黃瀉心湯之代謝動力學及藥物交互作用; I. Pharmacokinetics of Monohydroxyflavones, Anthraquinones and an-Huang-Xie-Xin-Tang II. Herb-Methotrexate Interactions

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题名:	單羥黃酮、蒽醌、三黃瀉心湯之代謝動力學及藥物交互作用;I. Pharmacokinetics of Monohydroxyflavones, Anthraquinones and an-Huang-Xie-Xin-Tang II. Herb-Methotrexate Interactions
作者:	夏麒盛;Chi-Sheng Shia
贡献者:	中國醫藥大學：藥物化學研究所博士班
关键词:	單羥黃酮;蒽;醌;三黃瀉心湯;代謝動力學;藥物交互作用;Monohydroxyflavones;Anthraquinones;Pharmacokinetics;San-Huang-Xie-Xin-Tang;Herb-Drug Interactions
日期:	2009-07-22
上传时间:	2009-08-13 09:37:13 (UTC+8)
摘要:	本研究探討單羥黃酮及蒽醌化合物之代謝及動力學。大白鼠口服5-Hydroxyflavone後，無法測得原形，主要以其glucuronide存在，而7-hydroxyflavone 口服後亦無原形，以其glucuronide 及sulfate存在於血中，顯示羥基位置影響黃酮之二相代謝歷程。Aloe-emodin、rhein、emodin等蒽醌口服後，皆主要以glucuronides 之形式存在，僅rhein尚有自由態存在於血中。三黃瀉心湯為臨床常用方劑，本研究以七位健康成年人之尿藥回收，比較水煎劑與濃縮散劑之生體可用率及生體相等性。結果顯示尿中並未檢出coptisine、palmatine、berberine，而baicalein、wogonin、emodin、aloe-emodin、rhein、chrysophanol主要皆以結合態代謝物 (sulfates/glucuronides) 存在於尿中、僅baicalein、rhein、chrysophanol尚有微量自由態存在。統計結果顯示，兩劑型間之各多酚成分不具生體相等性。胺甲葉酸 (Methotrexate，MTX) 為抗癌藥物，治療指數狹窄。本研究探討於不同時間併服三黃瀉心湯、大黃及黃芩水煎劑對MTX動力學之影響。結果顯示，於MTX給藥前 0.5 h、給藥後1.5 h、3.0 h併服三黃瀉心湯，皆顯著抑制MTX之排除。併服多劑量大黃、黃芩水煎劑亦顯著抑制MTX之排除。本研究另以Caco-2 細胞探討三黃瀉心湯、大黃及黃芩血清代謝物對MTX外排之影響，結果顯示此些血清代謝物皆顯著抑制MTX之外排，可以推論多酚結合態代謝物與MTX競爭腎小管細胞之MRPs (multidrug resistance proteins) 而導致藥物交互作用。本研究結果建議，若這些中藥與MTX同期服用時，必須嚴加注意病人安全。蒽醌多酚具許多優越的體外生物活性，本研究利用2,2-Azobis (2-amidinopropane) hydrochloride (AAPH) 誘導溶血，評估三黃瀉心湯血清代謝物之抗氧化活性，結果顯示具優越活性。因此，多酚結合態代謝物之生物活性值得重視。本研究另利用免疫缺陷小鼠，評估大黃之抗癌活性，結果顯示，口服大黃水煎劑顯著抑制A549細胞於肺部之生長，其抗癌機轉及臨床應用值得進一步研究。 This study investigated the metabolism and pharmacokinetics of monohydroxyflavones, anthraquinones and San-Huang-Xie-Xin-Tang (SHXXT). Following oral administrations of 5-hydroxyflavone and 7-hydroxyflavone in rats, the glucuronide of 5-hydroxyflavone and the sulfate/glucuronide of 7-hydroxyflavone were found in serum, whereas no traces of their parent forms were detected. These facts indicated that the position of hydroxyl group determined the fates of substrate toward glucuronidation or sulfation. Following oral administrations of aloe-emodin, rhein and emodin, their glucuronides were predominant in the blood, whereas their aglycones were not detected except for rhein. SHXXT is a popular Chinese medicine formula. By comparing urinary recovery in seven healthy volunteers, we evaluated the bioavailability and bioequivalence between traditional decoction and commercial powders of SHXXT. The results showed that alkaloids including coptisine, palmatine and berberine were not detected in urine. All polyphenols predominantly existed as their glucuronides, only traces of free forms of baicalein, rhein and chrysophanol were detected. Statistical analysis indicated that the bioavailabilities of the polyphenols of SHXXT in two dosage forms were essentially not bioeqivalent. Methotrexate (MTX) is a potent anticancer agent with narrow therapeutic range. This study investigated the effects of decoctions of SHXXT, Rhei Rhizoma (RR) and Scutellariae Radix (SR) on MTX pharmacokinetics in rats. Coadminstrations with SHXXT decoction at 0.5 h before and at 1.5 and 3.0 h after MTX dosing all resulted in significant inhibition of MTX elimination. Pretreatment with seven doses of RR, SR decoctions significantly inhibited MTX elimination. Futhermore, Caco-2 cell line was used to investigate the effect of serum metabolites of SHXXT, RR, SR on MTX efflux. The results showed that these serum metabolites significantly decreased the efflux of MTX from Caco-2 monolayer, suggesting that competition for MRPs (multidrug resistance proteins) may explain the herb-MTX interactions. In order to ensure the efficacy and safety of MTX, we suggest that concurrent use of MTX with SHXXT, RR and SR decoctions should be with caution. Anthraquinones have attracted increasing attention because of various beneficial in vitro biological activities. In order to evaluate the in vivo antioxidant activity of SHXXT, the serum metabolite was prepared, characterized and followed by evaluation of the effect on 2,2-Azobis(2-amidinopropane) hydrochloride (AAPH)-induced hemolysis. The results indicated that the serum metabolites of SHXXT exhibited significant free radical scavenging activity. The bioactivities of the conjugated metabolites of polyphenols are worthy for more studies. In addition, we also evaluated the anticancer effect of RR decoction using a mouse model. The results showed that RR is a potential anticancer remedy. The mechanism of action and clinical application of RR await further investigations.
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