Clinical Pharmacokinetics Laboratory, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.
WPI Nano Life Science Institute, Kanazawa University, Kanazawa, Japan.
Xenobiotica. 2021 Dec;51(12):1352-1359. doi: 10.1080/00498254.2021.2007553. Epub 2021 Nov 30.
Pirfenidone is a first-line drug for the treatment of idiopathic pulmonary fibrosis. The primary metabolic pathways of pirfenidone in humans are 5-hydroxylation and subsequent oxidation to 5-carboxylpirfenidone. The aims of this study were to determine the cytochrome P450 isoforms responsible for pirfenidone 5-hydroxylation and to evaluate their contributions in human liver microsomes (HLM).Among the recombinant P450 isoforms, CYP1A2, CYP2D6, CYP2C19, CYP2A6, and CYP2B6 were shown to catalyse the 5-hydroxylation of pirfenidone. Pirfenidone 5-hydroxylase activity by HLM was inhibited by α-naphthoflavone (by 45%), 8-methoxypsolaren (by 84%), tranylcypromine (by 53%), and quinidine (by 15%), which are CYP1A2, CYP1A2/CYP2A6/CYP2C19, CYP2A6/CYP2C19, and CYP2D6 inhibitors, respectively.In 17 individual HLM donors, pirfenidone 5-hydroxylase activity was significantly correlated with phenacetin -deethylase ( = 0.89, < 0.001) and -mephenytoin 4'-hydroxylase activities ( = 0.51, < 0.05), which are CYP1A2 and CYP2C19 marker activities, respectively.By using the relative activity factors, the contributions of CYP1A2, CYP2C19, and CYP2D6 to pirfenidone 5-hydroxylation in the human liver were 72.8%, 11.8%, and 8.9%, respectively.In conclusion, we clearly demonstrated the predominant P450 involved in pirfenidone 5-hydroxylation in the human liver is CYP1A2, with CYP2C19 and CYP2D6 playing a minor role.
吡非尼酮是治疗特发性肺纤维化的一线药物。在人体内，吡非尼酮的主要代谢途径为 5-羟化，随后氧化为 5-羧酸吡非尼酮。本研究旨在确定负责吡非尼酮 5-羟化的细胞色素 P450 同工酶，并评估其在人肝微粒体（HLM）中的作用。
在重组 P450 同工酶中，CYP1A2、CYP2D6、CYP2C19、CYP2A6 和 CYP2B6 被证明可催化吡非尼酮的 5-羟化。HLM 对吡非尼酮的 5-羟化酶活性被 α-萘黄酮（抑制 45%）、8-甲氧基青蒿素（抑制 84%）、曲安西龙（抑制 53%）和奎尼丁（抑制 15%）抑制，它们分别是 CYP1A2、CYP1A2/CYP2A6/CYP2C19、CYP2A6/CYP2C19 和 CYP2D6 的抑制剂。
在 17 名个体 HLM 供体中，吡非尼酮 5-羟化酶活性与苯乙酮脱乙基酶（ = 0.89， < 0.001）和 -美芬妥因 4'-羟化酶活性显著相关（ = 0.51， < 0.05），分别为 CYP1A2 和 CYP2C19 的标记酶活性。
通过使用相对活性因子，CYP1A2、CYP2C19 和 CYP2D6 对人肝中吡非尼酮 5-羟化的贡献率分别为 72.8%、11.8%和 8.9%。
总之，我们明确证明了 CYP1A2 是参与人肝中吡非尼酮 5-羟化的主要 P450，CYP2C19 和 CYP2D6 起次要作用。
