替扎尼定在体外主要由细胞色素P450 1A2代谢。
Tizanidine is mainly metabolized by cytochrome p450 1A2 in vitro.
作者信息
Granfors Marika T, Backman Janne T, Laitila Jouko, Neuvonen Pertti J
机构信息
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
出版信息
Br J Clin Pharmacol. 2004 Mar;57(3):349-53. doi: 10.1046/j.1365-2125.2003.02028.x.
AIMS
To identify the cytochrome p450 (CYP) enzyme(s) that catalyze the metabolism of tizanidine in vitro.
METHODS
The effect of CYP isoform inhibitors on the elimination of tizanidine was studied using pooled human liver microsomes. The metabolism of the drug by a range of human recombinant CYP isoforms was then investigated.
RESULTS
Incubation of tizanidine (80 nm) with human liver microsomes resulted in time- and NADPH-dependent substrate consumption with a half-life of 50 min, initial reaction velocity of 1.1 pmol x min-1 x mg-1 protein and intrinsic clearance of 17 ml x min-1 x kg-1. The predicted in vivo hepatic clearance (CLh) of tizanidine using the well-stirred and parallel-tube model was close (68% and 82%, respectively) to its estimated in vivo CLh. Fluvoxamine and furafylline strongly inhibited tizanidine metabolism. Inhibitors specific to isoforms other than CYP1A2 had no substantial effect. Recombinant CYP1A2 metabolized tizanidine to a substantial degree (35% in 45 min), but other recombinant CYPs had little metabolic capacity for the drug.
CONCLUSIONS
CYP1A2 is primarily responsible for the metabolism of tizanidine. CYP1A2 inhibitors may inhibit its metabolism also in vivo.
目的
鉴定在体外催化替扎尼定代谢的细胞色素P450（CYP）酶。
方法
使用人肝微粒体池研究CYP同工酶抑制剂对替扎尼定消除的影响。然后研究一系列人重组CYP同工酶对该药物的代谢情况。
结果
替扎尼定（80 nM）与人肝微粒体孵育导致底物消耗呈时间和NADPH依赖性，半衰期为50分钟，初始反应速度为1.1 pmol·min⁻¹·mg⁻¹蛋白，内在清除率为17 ml·min⁻¹·kg⁻¹。使用充分搅拌和平行管模型预测的替扎尼定体内肝清除率（CLh）与其估计的体内CLh接近（分别为68%和82%）。氟伏沙明和呋拉茶碱强烈抑制替扎尼定代谢。对CYP1A2以外的同工酶具有特异性的抑制剂没有实质性影响。重组CYP1A2能大量代谢替扎尼定（45分钟内代谢35%），但其他重组CYP对该药物的代谢能力很小。
结论
CYP1A2是替扎尼定代谢的主要负责酶。CYP1A2抑制剂在体内也可能抑制其代谢。
Zotero 插件