Relative importance of intestinal and hepatic glucuronidation-impact on the prediction of drug clearance.
OBJECTIVE
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 (fm(UGT)) was determined using P450 and UGT cofactors. Utility of hepatic CL(int) for the prediction of in vivo clearance was assessed.


RESULTS
fm(UGT) (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 CL(int,CYP) was higher than intestinal (average 15-fold). Hepatic CL(int,UGT) predicted on average 22% of observed in vivo CL(int); with the exception of raloxifene and troglitazone, where the prediction was only 3%.


CONCLUSIONS
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 fm(UGT) in vitro.
Cubitt
Helen E
HE
School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Stopford Building Oxford Road, Manchester, M13 9PT, UK.
Houston
J Brian
JB
Galetin
Aleksandra
A
D000408:Alamethicin / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D020719:Glucuronides / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006801:Humans; D007422:Intestines / Q000187:drug effects / Q000201:enzymology*; D007476:Ionophores / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008861:Microsomes / Q000187:drug effects* / Q000201:enzymology; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011237:Predictive Value of Tests; D013379:Substrate Specificity
D020719:Glucuronides; D007476:Ionophores; D004364:Pharmaceutical Preparations; D000408:Alamethicin; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase