title: The effect of genetic polymorphisms in UGT2B15 on the pharmacokinetic profile of sipoglitazar, a novel anti-diabetic agent.
abstract: OBJECTIVE
  Sipoglitazar was a novel, azolealkanoic acid derivative that possesses selective activity for the peroxisome proliferator-activated receptors (PPAR) PPARγ, PPARα, and PPARδ. The compound undergoes phase II biotransformation by conjugation catalyzed by UDP-glucuronosyltransferase (UGT). The aim of this analysis was to explore the influence of genetic polymorphism in UGT on the pharmacokinetics of sipoglitazar.
  
  
  METHODS
  Three preliminary phase I clinical pharmacology studies were conducted in tandem in healthy human subjects. Genotyping was undertaken in a total of 82 subjects in the phase I program for the purpose of genotyping UGT polymorphisms. Plasma samples were collected for up to 48 h post-dose to characterize the pharmacokinetic profile following a single oral dose of the drug.
  
  
  RESULTS
  Plasma concentrations of sipoglitazar and the distribution of dose-normalized individual values for area under the plasma concentration-time curve from time 0 to infinity (AUC(0-∞)) before any stratification were considerably skewed with a multi-modal distribution. The proportion of variability in AUC(0-∞) explained by UGT2B15 was 66.7 % (P < 0.0001); the addition of other genetic or demographic factors was not statistically significant. Subjects homozygous for the UGT2B15 D85Y variant (UGT2B15*2/*2) were exposed to greater plasma concentrations of sipoglitazar than subjects homozygous for the wild-type allele UGT2B15*1/*1 (3.26-fold higher) or heterozygous allele UGT2B15*1/*2 (2.16-fold higher).
  
  
  CONCLUSIONS
  These results indicate that sipoglitazar clearance is substantially modified by UGT2B15 enzyme variants, with higher exposure observed in the UGT2B15*2/*2 genotype group.
authors.affiliation: Takeda Pharmaceutical Company, 1-1, Doshomachi 4-Chome, Chuo-Ku, Osaka 540-8645, Japan. fran.stringer@takeda.com
authors.forename: Frances
authors.initials: F
authors.lastname: Stringer
authors.forename: Graham
authors.initials: G
authors.lastname: Scott
authors.forename: Marian
authors.initials: M
authors.lastname: Valbuena
authors.forename: Judith
authors.initials: J
authors.lastname: Kinley
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Nishihara
authors.forename: Richard
authors.initials: R
authors.lastname: Urquhart
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000704:Analysis of Variance; D019540:Area Under Curve; D001711:Biotransformation; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D006207:Half-Life; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D010597:Pharmacogenetics; D010641:Phenotype; D011110:Polymorphism, Genetic; D011422:Propionates / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D013844:Thiazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006113:United Kingdom; D055815:Young Adult
chemical_list: D007004:Hypoglycemic Agents; D011422:Propionates; D013844:Thiazoles; C572168:sipoglitazar; D014453:Glucuronosyltransferase; C472000:UDP-glucuronosyltransferase 2B15, human