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Vol. 301, Issue 1, 382-390, April 2002
Department of Molecular and Cellular Pathology, Ninewells Hospital
and Medical School, Dundee, Scotland (M.G.S., B.B.); and Department of
Physical and Metabolic Science, AstraZeneca Charnwood, Leics, England
(R.J.R.)
The glucuronidation of a number of commonly used hepatic uridine
diphosphate glucuronosyltransferase drug substrates has been studied in human tissue microsomes. Prediction of in vivo
hepatic drug glucuronidation from liver microsomal data yielded a
consistent 10-fold underprediction. Consideration of protein binding
was observed to be pivotal when predicting in vivo glucuronidation for
acid substrates. Studies using human intestinal microsomes demonstrated
the majority of drugs to be extensively glucuronidated such that the
intrinsic clearance (CLint) of ethinylestradiol (CLint = 1.3 µl/min/mg) was twice that obtained
using human liver microsomes (CLint = 0.7 µl/min/mg). The potential extrahepatic in vivo glucuronidation was
calculated for a range of drug substrates from human microsomal data.
These results indicate the contribution of intestinal drug
glucuronidation to systemic drug clearance to be much less than either
hepatic or renal glucuronidation. Therefore, data obtained with
intestinal microsomes may be misleading in the assessment of the
contribution of this organ to systemic glucuronidation. The use of
hepatocytes to assess metabolic stability for drugs predominantly
metabolized by glucuronidation was also investigated. Metabolic
clearances for a range of drugs obtained using fresh preparations of
human hepatocytes predicted accurately hepatic clearance reported in
vivo. The use of cryopreserved hepatocytes as an in vitro tool to
predict in vivo metabolism was also assessed with an excellent
correlation obtained for a number of extensively glucuronidated drugs
(R2 = 0.80, p < 0.001).
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