Raloxifene glucuronidation in human intestine, kidney and liver microsomes and in human liver microsomes genotyped for the UGT1A1*28 polymorphism

摘要

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-4u27-?-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.