Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China (X.Z., Q.P., H.W., X.Q., P.S., L.Z., G.G., L.Y.); Center for Systems Pharmacokinetics, Shanghai University of Traditional Chinese Medicine, Shanghai, China (X.Z., Q.P., H.W., X.Q., P.S., L.Z., G.G., L.Y.); College of Basic Medical Sciences, Dalian Medical University, Liaoning, China (H.M.); Shanghai Research Institute of Acupuncture and Meridian, Shanghai, China (H.M.); and Respiratory Medicine Department, Central Hospital Affiliated to Shenyang Medical College, Liaoning, China (M.M., S.X.).
Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China (X.Z., Q.P., H.W., X.Q., P.S., L.Z., G.G., L.Y.); Center for Systems Pharmacokinetics, Shanghai University of Traditional Chinese Medicine, Shanghai, China (X.Z., Q.P., H.W., X.Q., P.S., L.Z., G.G., L.Y.); College of Basic Medical Sciences, Dalian Medical University, Liaoning, China (H.M.); Shanghai Research Institute of Acupuncture and Meridian, Shanghai, China (H.M.); and Respiratory Medicine Department, Central Hospital Affiliated to Shenyang Medical College, Liaoning, China (M.M., S.X.)
Drug Metab Dispos. 2020 May;48(5):345-352. doi: 10.1124/dmd.119.089565. Epub 2020 Feb 21.
Doxophylline (DOXO) and theophylline are widely used as bronchodilators for treating asthma and chronic obstructive pulmonary disease, and DOXO has a better safety profile than theophylline. How DOXO's metabolism and disposition affect its antiasthmatic efficacy and safety remains to be explored. In this study, the metabolites of DOXO were characterized. A total of nine metabolites of DOXO were identified in vitro using liver microsomes from human and four other animal species. Among them, six metabolites were reported for the first time. The top three metabolites were theophylline acetaldehyde (M1), theophylline-7-acetic acid (M2), and etophylline (M4). A comparative analysis of DOXO metabolism in human using liver microsomes, S9 fraction, and plasma samples demonstrated the following: 1) The metabolism of DOXO began with a cytochrome P450 (P450)-mediated, rate-limiting step at the C ring and produced M1, the most abundant metabolite in human liver microsomes. However, in human plasma, the M1 production was rather low. 2) M1 was further converted to M2 and M4, the end products of DOXO metabolism in vivo, by non-P450 dismutase in the cytosol. This dismutation process also relied on the ratio of NADP/NADPH in the cell. These findings for the first time elucidated the metabolic sites and routes of DOXO metabolism in human. SIGNIFICANCE STATEMENT: We systematically characterized doxophylline metabolism using in vitro and in vivo assays. Our findings evolved the understandings of metabolic sites and pathways for methylxanthine derivatives with the aldehyde functional group.
二羟丙茶碱（DOXO）和茶碱被广泛用作治疗哮喘和慢性阻塞性肺疾病的支气管扩张剂，并且 DOXO 的安全性比茶碱更好。DOXO 的代谢和处置如何影响其抗哮喘疗效和安全性仍有待探索。在本研究中，我们对 DOXO 的代谢物进行了表征。使用来自人类和其他四种动物物种的肝微粒体在体外鉴定了 DOXO 的总共 9 种代谢物。其中，有 6 种代谢物是首次报道的。前三种代谢物是茶碱乙醛（M1）、茶碱-7-乙酸（M2）和乙茶碱（M4）。使用肝微粒体、S9 部分和血浆样本对 DOXO 在人体内的代谢进行比较分析，结果表明：1）DOXO 的代谢始于 C 环的细胞色素 P450（P450）介导的限速步骤，产生 M1，这是人类肝微粒体中最丰富的代谢物。然而，在人类血浆中，M1 的产生量相当低。2）M1 进一步通过细胞质中非 P450 歧化酶转化为 M2 和 M4，这是 DOXO 体内代谢的终产物。该歧化过程也依赖于细胞内 NADP/NADPH 的比值。这些发现首次阐明了 DOXO 在人体内的代谢部位和途径。意义陈述：我们使用体外和体内测定系统地表征了二羟丙茶碱的代谢。我们的研究结果发展了对具有醛官能团的甲基黄嘌呤衍生物的代谢部位和途径的认识。
