title: Induction of P450 3A1/2 and 2C6 by gemfibrozil in Sprague-Dawley rats.
abstract: Fibrates are a group of peroxisome proliferator-activated receptor α agonists used in the treatment of dyslipidemia; however, they have been reported 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.
authors: Medical School of Ningbo University, Ningbo 315211, China. yangjulin2002@126.com.
authors: Aiming
authors: A
authors: Liu
authors: Julin
authors: J
authors: Yang
authors: Xin
authors: X
authors: Zhao
authors: Xiaolan
authors: X
authors: Jiao
authors: Weihong
authors: W
authors: Zhao
authors: Qing
authors: Q
authors: Ma
authors: Zhiyuan
authors: Z
authors: Tang
authors: Renke
authors: R
authors: Dai
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis / Q000187:drug effects; D019389:Cytochrome P-450 CYP2D6 / Q000096:biosynthesis / Q000187:drug effects*; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis / Q000187:drug effects*; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D015248:Gemfibrozil / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D000960:Hypolipidemic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000187:drug effects*; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
chemical_list: D000960:Hypolipidemic Agents; D008565:Membrane Proteins; D001189:Aryl Hydrocarbon Hydroxylases; C119985:Cyp2d2 protein, rat; C465260:Cyp3a2 protein, rat; C465138:Cyp3a23-3a1 protein, rat; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D015248:Gemfibrozil