Induction of P450 3A1/2 and 2C6 by gemfibrozil in Sprague-Dawley rats
Induction of P450 3A1/2 and 2C6 by gemfibrozil in Sprague-Dawley rats
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吉非贝齐在 Sprague-Dawley 大鼠中诱导 P450 3A1/2 和 2C6
DOI：
10.1016/s1734-1140(11)70410-8
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发表时间：
2011-01-01
影响因子：
4.4
通讯作者：
Dai, Renke
中科院分区：
文献类型：
--
作者：
Liu, Aiming;Yang, Julin;Dai, Renke
Fibrates are a group of peroxisome proliferator-activated receptor alpha agonists used in the treatment of dyslipidemia; however, they have been repotted to cause species-related hepatocarcinogenesis and clinical myotoxicity. Gemfibrozil is one of the most commonly used fibrates, and it shows the highest risk for myotoxicity among the fibrates. The inhibitory drug-drug interaction mechanism associated with gemfibrozil has been explored recently, and the induction of human P450 3A4 and 2C8 has been reported. In this study, in vivo induction of rat P450 by gemfibrozil was studied in Sprague-Dawley rats. After the rats were dosed with gemfibrozil by oral gavage, microsomes were prepared. The metabolic activities of P450 3A1/2, 2C6, and 2D2 were assayed using probe substrates, and the systemic concentration of gemfibrozil during its administration was determined. P450 3A1/2 and 2C6 activities were induced 32-77 %. in the rats by gemfibrozil when the exposure concentration was in the clinical range. These data indicate that the inducibility of homologous P450 isoforms by gemfibrozil is similar in Sprague-Dawley rats and in humans. Inductive drug-drug interactions and inhibitory actions are involved in the co-administration of gemfibrozil with other drugs, which suggests the relevance for a fibrate-toxicology investigation.
