Intestinal glucuronidation metabolism may have a greater impact on oral bioavailability than hepatic glucuronidation metabolism in humans: a study with raloxifene, substrate for UGT1A1, 1A8, 1A9, and 1A10

Int J Pharm. 2009 Aug 13;378(1-2):140-1. doi: 10.1016/j.ijpharm.2009.05.044. Epub 2009 May 30.

Abstract

The kinetic impact of intestinal glucuronidation metabolism on oral bioavailability (F) was assessed using reported human data of raloxifene, of which oral bioavailability was only 2%. Kinetic analysis showed that presystemic intestinal availability (Fpg) was 5.4%, whereas fraction absorbed (Ff) and hepatic availability (Fh) were 63% and 59.3%, respectively. Thus, Fpg was the lowest among factors, which affect oral bioavailability. In addition, Fpg was much lower than Fh, suggesting that intestinal glucuronidation metabolism has a greater impact on oral bioavailability than hepatic glucuronidation metabolism. It has been reported that UDP-glucuronosyltransferase (UGT) 1A1, UGT1A8, UGT1A9, and UGT1A10 are enzymes for raloxifene glucuronidation, and UGT1A8 and UGT1A10 are absent in the human liver, whereas UGT1A1, UGT1A8, UGT1A9, and UGT1A10 are present in the human intestine. Therefore, it is also suggested that intestinal glucuronidation catalyzed by UGTs, particularly UGT1A8 and UGT1A10, may play important roles in the first-pass metabolism, causing low oral bioavailability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Biological Availability
  • Glucuronides / metabolism
  • Glucuronosyltransferase / metabolism*
  • Humans
  • Intestinal Mucosa / metabolism*
  • Intestines / enzymology
  • Liver / enzymology
  • Liver / metabolism
  • Raloxifene Hydrochloride / pharmacokinetics*
  • Selective Estrogen Receptor Modulators / pharmacokinetics*

Substances

  • Glucuronides
  • Selective Estrogen Receptor Modulators
  • Raloxifene Hydrochloride
  • Glucuronosyltransferase