Metabolism and Pharmacokinetics of 3-n-Butylphthalide (NBP) in Humans: The Role of Cytochrome P450s and Alcohol Dehydrogenase in Biotransformation
Metabolism and Pharmacokinetics of 3-n-Butylphthalide (NBP) in Humans: The Role of Cytochrome P450s and Alcohol Dehydrogenase in Biotransformation
复制标题
3-正丁基苯酞 (NBP) 在人体中的代谢和药代动力学：细胞色素 P450 和乙醇脱氢酶在生物转化中的作用
DOI：
10.1124/dmd.112.049684
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发表时间：
2013-02-01
影响因子：
3.9
通讯作者：
Chen, Xiaoyan
中科院分区：
文献类型：
--
作者：
Diao, Xingxing;Deng, Pan;Chen, Xiaoyan
3-n-丁苯酞（NBP）是目前用于治疗脑缺血的心血管药物。本研究旨在研究NBP在人体内的代谢、药代动力学和排泄，并确定主要代谢物形成的酶。口服200 mg NBP后，NBP发生广泛代谢，在人血浆和尿液中鉴定出23种代谢物。主要的代谢途径包括烷基侧链上的羟基化，特别是在3-、ω-和ω-碳上，以及进一步的氧化和偶联。大约81.6%的剂量从尿液中回收，主要是nbp -11-酸（m2 -2）和m2 -2的葡萄糖醛酸缀合物和单羟基化产物。10-酮-NBP （M2）、3-羟基-NBP （M3-1）、10-羟基-NBP （M3-2）和M2 -2是主要的循环代谢物，曲线下面积分别是NBP的1.6-、2.9-、10.3-和4.1倍。通过黑坎宁哈默氏菌的微生物转化获得了这四种代谢物的标准品。体外表型研究表明，多种细胞色素P450 （P450）亚型，特别是CYP3A4、2E1和1A2，参与了M3-1、M3-2和11-羟基nbp的形成。以M2 -2和11-羟基- nbp为底物，人体亚细胞组分实验发现，P450、乙醇脱氢酶和醛脱氢酶催化M2和M2 -2的生成。M2 -2的生成速度比M2快得多，且M2 -2在大鼠肝脏匀浆中可发生β-氧化生成邻苯二甲酸。总的来说，我们的研究表明，NBP在尿排泄前被多种酶吸收并广泛代谢为各种代谢物。
3-n-Butylphthalide (NBP) is a cardiovascular drug currently used for the treatment of cerebral ischemia. The present study aims to investigate the metabolism, pharmacokinetics, and excretion of NBP in humans and identify the enzymes responsible for the formation of major metabolites. NBP underwent extensive metabolism after an oral administration of 200 mg NBP and 23 metabolites were identified in human plasma and urine. Principal metabolic pathways included hydroxylation on alkyl side chain, particularly at 3-, ω-1-, and ω-carbons, and further oxidation and conjugation. Approximately 81.6% of the dose was recovered in urine, mainly as NBP-11-oic acid (M5-2) and glucuronide conjugates of M5-2 and mono-hydroxylated products. 10-Keto-NBP (M2), 3-hydroxy-NBP (M3-1), 10-hydroxy-NBP (M3-2), and M5-2 were the major circulating metabolites, wherein the areas under the curve values were 1.6-, 2.9-, 10.3-, and 4.1-fold higher than that of NBP. Reference standards of these four metabolites were obtained through microbial biotransformation by Cunninghamella blakesleana. In vitro phenotyping studies demonstrated that multiple cytochrome P450 (P450) isoforms, especially CYP3A4, 2E1, and 1A2, were involved in the formation of M3-1, M3-2, and 11-hydroxy-NBP. Using M3-2 and 11-hydroxy-NBP as substrates, human subcellular fractions experiments revealed that P450, alcohol dehydrogenase, and aldehyde dehydrogenase catalyzed the generation of M2 and M5-2. Formation of M5-2 was much faster than that of M2, and M5-2 can undergo β-oxidation to yield phthalide-3-acetic acid in rat liver homogenate. Overall, our study demonstrated that NBP was well absorbed and extensively metabolized by multiple enzymes to various metabolites prior to urinary excretion.