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

Purpose: To assess the extent of intestinal and hepatic glucuronidation in vitro and resulting implications on glucuronidation clearance prediction. Methods: Alamethicin activated human intestinal (HIM) and hepatic (HLM) microsomes were used to obtain intrinsic glucuronidation clearance (CL int,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. Results: 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 CL int,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 CL int,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%. Conclusion: 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. © 2009 Springer Science+Business Media, LLC.