Effects of UGT1A1*28 polymorphism on raloxifene pharmacokinetics and pharmacodynamics.

Trontelj, Jurij; Marc, Janja; Zavratnik, Andrej; Bogataj, Marija; Mrhar, Ale

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT? • Raloxifene exhibits large and unexplained interindividual pharmacokinetic variability (coefficient of variation 30–50%). • There is some evidence that UDP-glucuronosyltranferase 1A1 (UGT1A1) may play a key role in metabolic clearance of raloxifene. • UGT1A1 has a common genetic polymorphism, UGT1A1*28, that could lead to slower elimination of raloxifene and contribute to the high pharmacokinetic variability. WHAT THIS STUDY ADDS • Subjects with UGT1A1*28/*28 genotype exhibited a twofold higher raloxifene exposure compared with the hetero- and homozygotes for the wild-type allele. This indicates that raloxifene pharmacokinetics may be significantly affected by the UGT1A1*28 polymorphism. • It was also demonstrated that the *28 homozygotes gained a significantly greater increase in hip bone mineral density after 12 months' raloxifene treatment. AIMS 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.

RALOXIFENE; PHARMACOKINETICS; GENETIC polymorphisms; PHARMACODYNAMICS; BONE density; BILIRUBIN

British Journal of Clinical Pharmacology, 2009, Vol 67, Issue 4, p437

0306-5251

Academic Journal

10.1111/j.1365-2125.2009.03363.x