UGT2B17 genetic polymorphisms dramatically affect the pharmacokinetics of MK-7246 in healthy subjects in a first-in-human study

Clin Pharmacol Ther. 2012 Jul;92(1):96-102. doi: 10.1038/clpt.2012.20. Epub 2012 Jun 6.


MK-7246, an antagonist of the chemoattractant receptor on T helper type 2 (Th2) cells, is being developed for the treatment of respiratory diseases. In a first-in-human study, we investigated whether genetic polymorphisms contributed to the marked intersubject variability in the pharmacokinetics of MK-7246 and its glucuronide metabolite M3. Results from in vitro enzyme kinetic studies suggested that UGT2B17 is probably the major enzyme responsible for MK-7246 metabolism in both the liver and the intestine. As compared with those with the UGT2B17*1/*1 wild-type genotype, UGT2B17*2/*2 carriers, who possess no UGT2B17 protein, had 25- and 82-fold greater mean dose-normalized values of area under the plasma concentration-time curve (AUC) and peak concentration of MK-7246, respectively, and a 24-fold lower M3-to-MK-7246 AUC ratio. The apparent half-life of MK-7246 was not as variable between these two genotypes. Therefore, the highly variable pharmacokinetics of MK-7246 is attributable primarily to the impact of UGT2B17 genetic polymorphisms and extensive first-pass metabolism of MK-7246.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Administration, Oral
  • Adult
  • Area Under Curve
  • Carbolines / pharmacokinetics*
  • Double-Blind Method
  • Drug Monitoring
  • Genotype
  • Glucuronides / metabolism
  • Glucuronosyltransferase / genetics*
  • Half-Life
  • Humans
  • Male
  • Minor Histocompatibility Antigens
  • Pharmacogenetics / methods
  • Polymorphism, Genetic
  • Receptors, Antigen, T-Cell / antagonists & inhibitors


  • ((7R)-7-(((4-fluorophenyl)sulfonyl)(methyl)amino)-6,7,8,9-tetrahydropyrido(1,2-a)indol-10-yl)acetic acid
  • Carbolines
  • Glucuronides
  • Minor Histocompatibility Antigens
  • Receptors, Antigen, T-Cell
  • Glucuronosyltransferase
  • UGT2B17 protein, human