title: Drug-drug interaction of losartan and glimepiride metabolism by recombinant microsome CYP2C9*1, 2C9*3, 2C9*13, and 2C9*16 in vitro.
abstract: OBJECTIVE
  Co-administration of anti-hypertension and anti-diabetic drugs is common in clinical settings.
  
  
  METHODS
  In this study, we characterized the drug-drug interactions of losartan (LOS) and glimepiride (GLP) using recombinant cytochrome P450 (CYP) 2C9 enzymes (CYP2C9*1, CYP2C9*3, CYP2C9*13, and CYP2C9*16).
  
  
  RESULTS
  Metabolism of losartan by recombinant CYP2C9* 1, CYP2C9*3, CYP2C9*13, and CYP2C9* 16 was inhibited by glimepiride competitively with IC50 values of 0.669 ± 0.055 µM, 0.424 ± 0.032 µM, 2.557 ± 0.058 µM, and 0.667 ± 0.039 µM, respectively. The inhibitory effect of glimepiride on losartan metabolism by CYP2C9*13 was marginal. The apparent Ki value of glimepiride with CYP2C9*3 (0.0416 ± 0.0059 µM) was significantly lower than with CYP2C9*1 (0.1476 ± 0.0219 µM) and CYP2C9*16 (0.2671 ± 0.0456 µM). On the other hand, losartan weakly inhibited the hydroxylation of glimepiride by P450 2C9 enzymes competitively. The potencies for inhibition of glimepiride hydroxylation were determined to be CYP2C9*1~CYP2C9*3~CYP2C9*16 > CYP2C9*13 by 4 µM losartan. No significant inhibition was observed when 0.5 µM losartan was used.
  
  
  CONCLUSIONS
  Given these results, the potential inhibition of losartan metabolism by CYP2C9*3, CYP2C9*13, and CYP2C9*16 in vivo by glimepiride deserves further investigation. These results may provide valuable information for optimizing the anti-hypertension efficacy of losartan when glimepiride is co-administered to patients.
authors.forename: Sai-Zhen
authors.initials: SZ
authors.lastname: Chen
authors.forename: Pei-Pei
authors.initials: PP
authors.lastname: Pan
authors.forename: Lei-Bin
authors.initials: LB
authors.lastname: Shen
authors.forename: Shan-Shan
authors.initials: SS
authors.lastname: Xu
authors.forename: Da-Peng
authors.initials: DP
authors.lastname: Dai
authors.forename: Pei-Wu
authors.initials: PW
authors.lastname: Geng
authors.forename: Jie
authors.initials: J
authors.lastname: Cai
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Cai
authors.forename: Guo-Xin
authors.initials: GX
authors.lastname: Hu
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000009:adverse effects / Q000378:metabolism*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D001711:Biotransformation; D065729:Cytochrome P-450 CYP2C9; D004347:Drug Interactions; D006801:Humans; D006900:Hydroxylation; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000378:metabolism*; D007700:Kinetics; D019808:Losartan / Q000009:adverse effects / Q000378:metabolism*; D008861:Microsomes / Q000201:enzymology*; D010084:Oxidation-Reduction; D010597:Pharmacogenetics; D010641:Phenotype; D011110:Polymorphism, Genetic; D011994:Recombinant Proteins / Q000378:metabolism; D018570:Risk Assessment; D012307:Risk Factors; D013453:Sulfonylurea Compounds / Q000009:adverse effects / Q000378:metabolism*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D007004:Hypoglycemic Agents; D011994:Recombinant Proteins; D013453:Sulfonylurea Compounds; C057619:glimepiride; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D019808:Losartan