izpis_h1_title_alt

Raloxifene glucuronidation in human intestine, kidney and liver microsomes and in human liver microsomes genotyped for the UGT1A1*28 polymorphism
Trdan Lušin, Tina (Author), Trontelj, Jurij (Author), Mrhar, Aleš (Author)

URLURL - Presentation file, Visit http://dmd.aspetjournals.org/content/early/recent This link opens in a new window

Abstract
Raloxifene, a selective estrogen receptor modulator, exhibits quite large inter individual variability in pharmacokinetics and pharmacodynamics. In women, raloxifene is extensively metabolized by different isoforms of UDP-glucuronosyltransferase (UGT) to its glucuronides. In order to gain an insight into intestine, kidney, liver and lung glucuronidation of raloxifene, human microsomes of all tested organs were used. Raloxifene-6-?-glucuronide (M1) formation followed the Michaelis-Menten kinetics in intestinal, kidney and liver microsomes, meanwhile raloxifene-4'-?-glucuronide (M2) formation followed the substrate inhibition kinetics. Human lung microsomes did not show any glucuronidation activity. The intrinsic tissue clearances for kidney, intestine and liver were 3.4, 28.1 and 39.6 mLmin-1kg-1, respectively. The aim of our in vitro study was to explain the mechanism behind the observed influence of UGT1A1*28 polymorphism on raloxifene pharmacokinetics in a small-sized in vivo study by Trontelj et al. Incubation of raloxifene with human liver microsomes genotyped for UGT1A1*28 showed a significantly reduced metabolic clearance towards M1 in microsomes from donors with *28 allele. On the contrary, no significant genotype influence was observed on the formation of M2 due to the high variability in estimated apparent kinetic parameters, although a clear trend towards lower glucuronidation activities was observed when UGT1A1*28 polymorphism was present. The intrinsic liver clearances of both homozygotes differed significantly, while the clearance of heterozygotes did not differ from the wild-type and the mutated homozygotes. In conclusion, our results show the high importance of the liver and intestine in raloxifene glucuronidation. Moreover, the significant influence of UGT1A1*28 polymorphismon metabolism of raloxifene was confirmed.

Language:English
Keywords:raloksifen, UGT1A1*28, polimorfizem, farmakokinetika
Work type:Not categorized (r6)
Tipology:1.01 - Original Scientific Article
Organization:FFA - Faculty of Pharmacy
Year:2011
Number of pages:str. 2347-2354
Numbering:Vol. 39, no. 12
UDC:615.015
ISSN on article:0090-9556
DOI:10.1124/dmd.111.041897 Link is opened in a new window
COBISS.SI-ID:3091313 Link is opened in a new window
Views:1067
Downloads:240
Metadata:XML RDF-CHPDL DC-XML DC-RDF
 
Average score:(0 votes)
Your score:Voting is allowed only to logged in users.
:
Share:AddThis
AddThis uses cookies that require your consent. Edit consent...

Record is a part of a journal

Title:Drug metabolism and disposition
Shortened title:Drug metab. dispos.
Publisher:American Society for Pharmacology and Experimental Therapeutics, etc.
ISSN:0090-9556
COBISS.SI-ID:26791936 This link opens in a new window

Similar documents

Similar works from RUL:
Similar works from other Slovenian collections:

Comments

Leave comment

You have to log in to leave a comment.

Comments (0)
0 - 0 / 0
 
There are no comments!

Back