title: PPARα-dependent increase of mouse urine output by gemfibrozil and fenofibrate.
abstract: While gemfibrozil and fenofibrate are prescribed for anti-dyslipidemia treatment, a rational basis for the use of these drugs for treatment of dyslipidemia with concurrent metabolic syndrome has not been established. In this study, wild-type and Pparα-null mice were fed gemfibrozil- or fenofibrate-containing diets for 14 days. Urine output (24 h) was monitored, and urine, serum, and liver and kidney tissues were subjected to toxicity assessment. A 2-month challenge followed by a 2-week wash-out was performed for gemfibrozil to determine urine output and the potential toxicity. A therapeutically equivalent dose of gemfibrozil was more effective than fenofibrate in increasing urine output. This regulatory effect was not observed in Pparα-null mice. In contrast, hepatomegaly induced by fenofibrate was more pronounced than that of gemfibrozil. No significant toxicity was observed in liver or kidney in the 2-month treatment with gemfibrozil. These data demonstrated PPARα mediates the increased urine output by fibrates. Considering the relative action on hepatomegaly and the regulatory effect on urine output, gemfibrozil may be the preferable drug to increase urine output. These results revealed a new pharmacodynamic effect of clinically prescribed PPARα agonists and suggested the potential value of gemfibrozil in modification of blood pressure.
authors.affiliation: a Medical School of Ningbo University, Ningbo 315211, China.
authors.forename: Danjun
authors.initials: D
authors.lastname: Song
authors.affiliation: a Medical School of Ningbo University, Ningbo 315211, China.
authors.forename: Min
authors.initials: M
authors.lastname: Luo
authors.affiliation: a Medical School of Ningbo University, Ningbo 315211, China.
authors.forename: Manyun
authors.initials: M
authors.lastname: Dai
authors.affiliation: a Medical School of Ningbo University, Ningbo 315211, China.
authors.forename: Shizhong
authors.initials: S
authors.lastname: Bu
authors.affiliation: b The Affiliated Hospital of Medical College of Ningbo University, Ningbo 315020, China.
authors.forename: Weihua
authors.initials: W
authors.lastname: Wang
authors.affiliation: b The Affiliated Hospital of Medical College of Ningbo University, Ningbo 315020, China.
authors.forename: Burong
authors.initials: B
authors.lastname: Zhang
authors.affiliation: c Laboratory of Metabolism, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.affiliation: a Medical School of Ningbo University, Ningbo 315211, China.
authors.forename: Aiming
authors.initials: A
authors.lastname: Liu
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000450:Aldosterone / Q000097:blood; D000818:Animals; D001127:Arginine Vasopressin / Q000097:blood; D001219:Aspartate Aminotransferases / Q000097:blood; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000097:blood; D004232:Diuretics / Q000494:pharmacology*; D011345:Fenofibrate / Q000009:adverse effects / Q000494:pharmacology*; D015248:Gemfibrozil / Q000009:adverse effects / Q000494:pharmacology*; D006529:Hepatomegaly / Q000139:chemically induced; D006706:Homeostasis; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D047493:PPAR alpha / Q000378:metabolism*
chemical_list: D004232:Diuretics; D047493:PPAR alpha; D001127:Arginine Vasopressin; D000450:Aldosterone; D003404:Creatinine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D015248:Gemfibrozil; D011345:Fenofibrate
keywords: PPARα; débit urinaire; fenofibrate; fénofibrate; gemfibrozil; urine output