title: In vitro and in vivo drug-drug interaction of losartan and glimepiride in rats and its possible mechanism.
abstract: BACKGROUND
  Losartan and glimepiride are commonly used drugs to treat chronic diseases of hypertension and diabetes; they are both substrates of CYP2C9. The aim of the present study was to investigate the possible interaction of losartan and glimepiride both in vitro (rat liver microsomes) and in vivo (healthy Sprague-Dawley rats).
  
  
  METHODS
  In rat liver microsomes, 1-10 μmol/l losartan and glimepiride were coincubated, and the inhibitory effect was analyzed. In the subsequent pharmacokinetic study, 15 healthy Sprague-Dawley rats received administrations of 5 mg/kg losartan or 1 mg/kg glimepiride or a coadministration.
  
  
  RESULTS
  In the rat liver microsome system, glimepiride showed a slight inhibition of losartan at concentrations of 1-10 μmol/l, whereas losartan exhibited no inhibitory effect on glimepiride. In vivo, glimepiride did not modify the plasma concentration of losartan and its metabolite E-3174. The alteration of an increased AUC and Cmax was observed in the pharmacokinetic parameters of glimepiride and hydroxy glimepiride.
  
  
  CONCLUSIONS
  Glimepiride did not affect losartan pharmacokinetics in rats, while losartan potently altered glimepiride metabolism; this result was inconsistent with the in vitro outcome. The mechanism requires further investigation. In clinical settings, attention should be paid to the interaction of these two drugs in the human body as well as the possible adverse reactions of glimepiride.
authors.affiliation: Department of Pharmacy, Taizhou Central Hospital, Taizhou, PR China.
authors.forename: Sai-Zhen
authors.initials: SZ
authors.lastname: Chen
authors.forename: Pei-Pei
authors.initials: PP
authors.lastname: Pan
authors.forename: Shuang-Hu
authors.initials: SH
authors.lastname: Wang
authors.forename: Jun
authors.initials: J
authors.lastname: Luo
authors.forename: Guo-Xin
authors.initials: GX
authors.lastname: Hu
authors.forename: Shan-Shan
authors.initials: SS
authors.lastname: Xu
authors.forename: Lu
authors.initials: L
authors.lastname: Zhang
authors.forename: Yin-Fei
authors.initials: YF
authors.lastname: Yu
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D019808:Losartan / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013453:Sulfonylurea Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000959:Antihypertensive Agents; D007004:Hypoglycemic Agents; D013453:Sulfonylurea Compounds; C057619:glimepiride; D003577:Cytochrome P-450 Enzyme System; C507848:CYP2C9 protein, rat; D019808:Losartan