UGT1A1*28 polymorphism influences glucuronidation of bazedoxifene.

Bazedoxifene is used for the prevention and treatment of osteoporosis. After peroral application, bazedoxifene is metabolized by UDP-glucuronosyltransferases (UGTs) to bazedoxifene-4'-glucuronide (M4) and bazedoxifene-5-glucuronide (M5). It has already been shown that a relatively common UGT1A128 polymorphism can considerably affect raloxifene pharmacokinetics and pharmacodynamics. As pharmacokinetics of bazedoxifene and raloxifene are very similar, the influence of UGT1A128 polymorphism on metabolism of bazedoxifene was investigated by genotyped microsomes. Our results indicate an influence of UGT1A1*28 allele on the formation clearance of both bazedoxifene metabolites. The decreased metabolic clearance was most pronounced in microsomes from polymorphic homozygote (*28/28) where a 7 to 10-fold lower metabolic clearance was observed for both metabolites compared to other genotypes. In conclusion, the significant UGT1A128 genotype effect on bazedoxifene intrinsic metabolic clearance indicates that this subject is worth further exploration in vivo and provides valuable information research in this field.