The role of hepatic and extrahepatic UDP-glucuronosyltransferases in human drug metabolism.

Abstract:

:At present, the methods and enzymology of the UDP-glucuronosyltransferases (UGTs) lag behind that of the cytochromes P450 (CYPs). About 15 human UGTs have been identified, and knowledge about their regulation, substrate selectivity, and tissue distribution has progressed recently. Alamethicin has been characterized as a treatment to remove the latency of microsomal glucuronidations. Most UGT isoforms appear to have a distinct hepatic and/or extrahepatic expression, resulting in significant expression in kidney, intestine, and steroid target tissues. The gastrointestinal tract possesses a complex expression pattern largely containing members of the UGT1A subfamily. Thus, these forms are poised to participate in the first pass metabolism of oral drugs. The authors and others have identified a significant expression of UGT1A1 in human small intestine, an enzyme possessing considerable allelic variability and a polymorphic expression pattern in intestine. Intestinal glucuronidation therefore plays a major role not only in first pass metabolism, but also in the degree of interindividual variation in overall oral bioavailability. Due to issues such as significant genetic variability and tissue localization in first-pass organs, clearance due to UGT1A1 should be minimized for new drugs.

journal_name

Drug Metab Rev

journal_title

Drug metabolism reviews

authors

Fisher MB,Paine MF,Strelevitz TJ,Wrighton SA

doi

10.1081/dmr-120000653

keywords:

subject

Has Abstract

pub_date

2001-08-01 00:00:00

pages

273-97

issue

3-4

eissn

0360-2532

issn

1097-9883

journal_volume

33

pub_type

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