Effects of UGT1A1*28 polymorphism on raloxifene pharmacokinetics and pharmacodynamics.
OBJECTIVE
Raloxifene concentrations were reported to correlate approximately with serum bilirubin levels. Bilirubin is a typical UGT1A1 substrate. Based on these facts, we postulated a hypothesis that UGT1A1 is the key enzyme for metabolic clearance of raloxifene and that the common UGT1A1*28 polymorphism significantly contributes to the large pharmacokinetic variability of raloxifene.


METHODS
Serum samples from postmenopausal osteoporotic patients treated with raloxifene were assayed for the concentrations of raloxifene and its glucuronides by liquid chromatography-mass spectrometry-mass spectrometry. The same samples were also genotyped for the presence of UGT1A1*28 polymorphism by the single-strand conformation polymorphism method. The pharmacodynamic effect was evaluated by measuring the change in bone mineral density (BMD) in femoral neck, hip and lumbar spine after 12 months' raloxifene therapy.


RESULTS
Patients homozygous for the *28 allele showed significantly, twofold higher raloxifene glucuronide concentrations compared with the hetero- and homozygotes for the wild-type allele: 558 +/- 115 nmol l(-1) compared with 295 +/- 43 nmol l(-1), respectively (P = 0.012). This indicates a higher raloxifene exposure in the *28/*28 group. Consequently, a significantly greater increase in hip BMD was observed in subjects homozygous for the *28 allele compared with the group carrying at least one copy of the wild-type allele: 4.4 +/- 2.4% compared with 0.3 +/- 1.4% (P = 0.035).


CONCLUSIONS
In this study it is shown that a relatively common UGT1A1*28 polymorphism may considerably influence raloxifene pharmacokinetics and pharmacodynamics. Underlying mechanisms and clinical implications of our findings are also discussed.
Trontelj
Jurij
J
Faculty of Pharmacy, Department for Biopharmacy and Pharmacokinetics, University of Ljubljana, Ljubljana, Slovenia. jurij.trontelj@ffa.uni-lj.si
Marc
Janja
J
Zavratnik
Andrej
A
Bogataj
Marija
M
Mrhar
Ales
A
D000328:Adult; D000368:Aged; D015519:Bone Density / Q000187:drug effects*; D050071:Bone Density Conservation Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D015663:Osteoporosis, Postmenopausal / Q000188:drug therapy*; D011110:Polymorphism, Genetic; D020849:Raloxifene Hydrochloride / Q000493:pharmacokinetics* / Q000627:therapeutic use; D053719:Tandem Mass Spectrometry; D016896:Treatment Outcome; D055815:Young Adult; D000099148:UGT1A1 Enzyme
D050071:Bone Density Conservation Agents; D014453:Glucuronosyltransferase; D020849:Raloxifene Hydrochloride; D000099148:UGT1A1 Enzyme