目的 研究木蘭花堿在大鼠體內(nèi)外的主要代謝產(chǎn)物及代謝途徑。方法 SD大鼠ig木蘭花堿（50 mg/kg），收集0~24 h尿液和糞便，0~6 h膽汁以及1、2、4、6、8 h血漿；體外代謝采用肝微粒體溫孵系統(tǒng)和腸菌培養(yǎng)液。利用LC-MS/MS對生物樣品中的原型藥及代謝產(chǎn)物進(jìn)行鑒定。采用Agilent TC-C₁₈色譜柱（150 mm×4.6 mm，5 μm），以乙腈-0.1%甲酸水溶液為流動(dòng)相梯度洗脫，體積流量1.0 mL/min，柱溫30℃。質(zhì)譜采用電噴霧電離源（ESI），正離子采集模式；掃描范圍m/z100~1 000。根據(jù)藥物體內(nèi)代謝規(guī)則，結(jié)合木蘭花堿的色譜保留時(shí)間和多級質(zhì)譜碎片離子特征，推測其代謝產(chǎn)物的結(jié)構(gòu)。結(jié)果 給藥后生物樣品中共鑒定出12個(gè)代謝產(chǎn)物，其中Ⅰ相代謝產(chǎn)物8個(gè)，Ⅱ相代謝產(chǎn)物4個(gè)。主要的代謝途徑為羥基化、去甲基化、脫氫作用、酮基化、葡萄糖化、葡萄糖醛酸化及硫酸酯化。結(jié)論 木蘭花堿在體內(nèi)可發(fā)生Ⅰ相和Ⅱ相代謝，腸道菌群和肝藥酶可催化木蘭花堿發(fā)生Ⅰ相代謝轉(zhuǎn)化，Ⅱ相代謝存在于腸道以外部位，最有可能的部位是肝臟。

Objective To study the main metabolites and metabolic pathway of magnoflorine in vitro and in vivo. Methods SD rats were given magnolithine by single gavage at a dose of 50 mg/kg. Urine and feces form 0 h to 24 h, bile form 0 h to 6 h, and plasma samples at 1, 2, 4, 6, and 8 h after administration were collected. In vitro metabolism was incubated with rat liver microsome and intestinal flora. The metabolites were analyzed and identified by the high-resolution HPLC-MS/MS technique. Chromatographic separation was achieved on Agilent TC-C₁₈ chromatograph column (150 mm×4.6 mm, 5 μm). The mobile phase consisted of 0.1% formic acid-acetonitrile with a flow rate of 1.0 mL/min, and the column temperature was 30℃. The mass spectra were obtained in positive ion modes with electrospray ionization (ESI), the scanning range was m/z 100-1 000. The structures of metabolites were elucidated by the metabolic rules of drugs in vivo, and combined with the chromatographic retention time of magnoflorine and the characteristics of fragment ions of MS. Results A total of 12 metabolites were identified in each sample, including 8 phase I metabolites and 4 phase II metabolites. The pathways to these metabolites were hydroxylation, demethylation, dehydrogenation, ketoylation, gluconylation, glucuronide conjugation, and sulfation. Conclusion Magnoflorine could produce metabolic reaction of phase I and phase II in rat. Intestinal flora and liver drug enzymes could catalyze the phase I metabolism of magnoflorine, and phase II metabolism exists outside the intestine, and the most likely site is the liver.

R284.1

國家自然科學(xué)基金項(xiàng)目（81673680）