Species differences in inhibition potential of nonsteroidal anti-inflammatory drugs against estradiol 3beta-glucuronidation between rats, dogs, and humans

J Pharm Sci. 2008 Jul;97(7):2805-10. doi: 10.1002/jps.21185.


Differences in the inhibitory potentials against UDP-glucuronosyltransferase (UGT) between species have been reported only rarely, even though the information would be useful for the precise characterization of drug candidates. In this study, the inhibition potentials of nonsteroidal anti-inflammatory drugs (NSAIDs) against UGT-catalyzed estradiol 3beta-glucuronidation (E3G) in the liver microsomes of rats, dogs, and humans were compared. Rat liver microsomes (RLMs) and human liver microsomes (HLMs) exhibited homotropic activation kinetics with S(50) values of 22 and 12 microM, respectively. However, dog liver microsomes (DLMs), exhibited Michaelis-Menten kinetics with no activation. Among the NSAIDs investigated (diclofenac, diflunisal, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, mefenamic acid, niflumic acid, and sulindac), only niflumic acid and mefenamic acid inhibited E3G potently in all three species. The IC(50) values of NSAIDs against E3G in RLMs and HLMs were within a threefold difference of each other, while those in DLMs was more than three times higher than the other two. In conclusion, RLMs showed an inhibitory pattern similar to that of HLMs, whereas DLMs presented a distinct pattern. These results indicate that a rat animal model would be useful for evaluating the inhibitory potentials of drugs against estradiol glucuronidation, but a dog model would not.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Dogs
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Estradiol / metabolism*
  • Estradiol / pharmacology
  • Glucuronosyltransferase / antagonists & inhibitors*
  • Humans
  • In Vitro Techniques
  • Microsomes, Liver / drug effects*
  • Microsomes, Liver / enzymology
  • Molecular Structure
  • Rats
  • Species Specificity
  • Structure-Activity Relationship


  • Anti-Inflammatory Agents, Non-Steroidal
  • Enzyme Inhibitors
  • Estradiol
  • UGT1A1 enzyme
  • Glucuronosyltransferase