title: Influence of CYP2C9 gene polymorphisms on response to glibenclamide in type 2 diabetes mellitus patients.
abstract: OBJECTIVE
  The antidiabetic drug glibenclamide is metabolized by the enzyme cytochrome P450 2C9 (CYP2C9) encoded by the polymorphic gene CYP2C9. Previous studies involving healthy volunteers have shown a significant influence of variant CYP2C9 genotypes on glibenclamide metabolism. The aim of this study was to investigate the influence of genetic polymorphisms of CYP2C9 on the response to glibenclamide and on glibenclamide plasma levels in type 2 diabetes mellitus patients.
  
  
  METHODS
  The study cohort consisted of type 2 diabetes mellitus patients (n = 80) on regular therapy with glibenclamide either alone or with concomitant metformin. Plasma levels of glibenclamide were estimated by reverse phase high pressure liquid chromatography. The variant alleles of CYP2C9, namely CYP2C9 *2 and *3, were identified by PCR-restricted fragment length polymorphism. The plasma levels of glibenclamide and occurrences of hypoglycemic adverse effects with their severity were compared between the genotype groups.
  
  
  RESULTS
  Of the 80 patients (61 males, 19 females), 78 were on concomitant treatment with two drugs, namely, glibenclamide and metformin, and two were on monotherapy with glibenclamide. There was a significant association (p < 0.001) between genotype status of CYP2C9 and the control of diabetes in patients receiving treatment with glibenclamide. There were no statistically significant differences in hypoglycemic adverse effects between the genotype groups.
  
  
  CONCLUSIONS
  The type 2 diabetes mellitus patients participating in this study with variant genotypes of CYP2C9 were found to respond better to treatment with glibenclamide than those with the normal genotype. The variant genotype CYP2C9 *1/*3 did not significantly influence the hypoglycemic adverse effects among those patients on long-term glibenclamide treatment.
authors.affiliation: Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry 605006, India. surenmbbs@gmail.com
authors.forename: A
authors.initials: A
authors.lastname: Surendiran
authors.forename: S C
authors.initials: SC
authors.lastname: Pradhan
authors.forename: Aparna
authors.initials: A
authors.lastname: Agrawal
authors.forename: D K S
authors.initials: DK
authors.lastname: Subrahmanyam
authors.forename: S
authors.initials: S
authors.lastname: Rajan
authors.forename: D
authors.initials: D
authors.lastname: Anichavezhi
authors.forename: C
authors.initials: C
authors.lastname: Adithan
mesh_terms: D000483:Alleles; D054458:Amplified Fragment Length Polymorphism Analysis; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D015331:Cohort Studies; D065729:Cytochrome P-450 CYP2C9; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D004359:Drug Therapy, Combination; D005260:Female; D056726:Genetic Association Studies; D005905:Glyburide / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D006943:Hyperglycemia / Q000517:prevention & control; D007003:Hypoglycemia / Q000139:chemically induced / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007194:India; D008297:Male; D050216:Metabolic Detoxication, Phase I; D008687:Metformin / Q000627:therapeutic use; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012720:Severity of Illness Index
chemical_list: D007004:Hypoglycemic Agents; D008687:Metformin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D005905:Glyburide