Non-steroidal anti-inflammatory drugs interact with testosterone glucuronidation

Steroids. 2009 Nov;74(12):971-7. doi: 10.1016/j.steroids.2009.07.004. Epub 2009 Jul 28.

Abstract

Testosterone and epitestosterone are secreted mainly as glucuronide metabolites and the urinary ratio of testosterone glucuronide to epitestosterone glucuronide, often called T/E, serves as a marker for possible anabolic steroids abuse by athletes. UDP-glucuronosyltransferase (UGT) 2B17 is the most important catalyst of testosterone glucuronidation. The T/E might be affected by drugs that interact with UGT2B17, or other enzymes that contribute to testosterone glucuronidation. Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used by sportsmen and we have examined the effect of two NSAIDs, diclofenac and ibuprofen, on testosterone and epitestosterone glucuronidation in human liver microsomes. In parallel, we have studied the inhibitory effect of these NSAIDs on recombinant UGT2B17 and UGT2B15, as well as other human hepatic UGTs that revealed low but detectable testosterone glucuronidation activity, namely UGT1A3, UGT1A4, UGT1A9 and UGT2B7. Both diclofenac and ibuprofen inhibited testosterone glucuronidation in microsomes, as well as UGT2B15 and UGT2B17. Interestingly, UGT2B15 was more sensitive than UGT2B17 to the two drugs, particularly to ibuprofen. Human liver microsomes lacking functional UGT2B17 exhibited significantly higher sensitivity to ibuprofen, suggesting that UGT2B15 plays a major role in the residual testosterone glucuronidation activity in UGT2B17-deficient individuals. Nonetheless, a minor contribution of other UGTs, particularly UGT1A9, to testosterone glucuronidation in such individuals cannot be ruled out at this stage. The epitestosterone glucuronidation activity of human liver microsomes was largely insensitive to ibuprofen and diclofenac. Taken together, the results highlight potential interactions between NSAIDs and androgen glucuronidation with possible implications for the validity of doping tests.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Inflammatory Agents, Non-Steroidal / metabolism
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Diclofenac / metabolism
  • Diclofenac / pharmacology
  • Genotype
  • Glucuronides / metabolism*
  • Glucuronosyltransferase / antagonists & inhibitors
  • Glucuronosyltransferase / genetics
  • Glucuronosyltransferase / metabolism
  • Humans
  • Ibuprofen / metabolism
  • Ibuprofen / pharmacology
  • Liver / cytology
  • Microsomes / drug effects
  • Microsomes / metabolism
  • Minor Histocompatibility Antigens
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Testosterone / metabolism*

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Glucuronides
  • Minor Histocompatibility Antigens
  • Recombinant Proteins
  • Diclofenac
  • Testosterone
  • Glucuronosyltransferase
  • UGT2B17 protein, human
  • Ibuprofen