Pharmaceutical Research

, 26:1073 | Cite as

Relative Importance of Intestinal and Hepatic Glucuronidation—Impact on the Prediction of Drug Clearance

  • Helen E. Cubitt
  • J. Brian Houston
  • Aleksandra Galetin
Research Paper



To assess the extent of intestinal and hepatic glucuronidation in vitro and resulting implications on glucuronidation clearance prediction.


Alamethicin activated human intestinal (HIM) and hepatic (HLM) microsomes were used to obtain intrinsic glucuronidation clearance (CLint,UGT) for nine drugs using substrate depletion. The in vitro extent of glucuronidation (fmUGT) was determined using P450 and UGT cofactors. Utility of hepatic CLint for the prediction of in vivo clearance was assessed.


fmUGT (8–100%) was comparable between HLM and HIM with the exception of troglitazone, where a nine-fold difference was observed (8% and 74%, respectively). Scaled intestinal CLint,UGT (per g tissue) was six- and nine-fold higher than hepatic for raloxifene and troglitazone, respectively, and comparable to hepatic for naloxone. The remaining drugs had a higher hepatic than intestinal CLint,UGT (average five-fold). For all drugs with P450 clearance, hepatic CLint,CYP was higher than intestinal (average 15-fold). Hepatic CLint,UGT predicted on average 22% of observed in vivo CLint; with the exception of raloxifene and troglitazone, where the prediction was only 3%.


Intestinal glucuronidation should be incorporated into clearance prediction, especially for compounds metabolised by intestine specific UGTs. Alamethicin activated microsomes are useful for the assessment of intestinal glucuronidation and fmUGT in vitro.


clearance prediction glucuronidation intestine 



intrinsic clearance


intrinsic clearance corrected for non-specific protein binding


intrinsic clearance by glucuronidation


intrinsic clearance by cytochrome P450 metabolism


fraction metabolised by glucuronidation


fraction unbound from protein in the incubation


fraction unbound in the blood


fraction unbound in the plasma


human intestinal microsomes


human liver microsomes


root mean squared error


blood to plasma concentration ratio


uridine diphosphate glucuronosyltransferase



The Authors would like to thank Sue Murby and Dr David Hallifax (University of Manchester) for valuable assistance with the LC-MS/MS.

The work was funded by a consortium of pharmaceutical companies (GlaxoSmithKline, Lilly, Novartis, Pfizer and Servier) within the Centre for Applied Pharmacokinetic Research at the University of Manchester. Part of this study was presented at the 10th ISSX Meeting, May 18–21, 2008, Vienna, Austria.


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Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Helen E. Cubitt
    • 1
  • J. Brian Houston
    • 1
  • Aleksandra Galetin
    • 1
  1. 1.School of Pharmacy and Pharmaceutical SciencesUniversity of ManchesterManchesterUK

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