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 exhibits a large and unexplained interindividual variability in its pharmacokinetics and pharmacodynamics. The aim of our study was to identify transporters involved in the efflux of raloxifene and its glucuronide metabolites by various in vitro models and by an in vivo study to explore the possible involvement of P-glycoprotein (Pgp), multidrug resistance-associated protein (MRP)1, MRP2, MRP3, and breast cancer resistance protein in the observed high interindividual variability. Experiments with the parallel artificial membrane permeability assay showed the highest passive permeability for raloxifene, followed by raloxifene-6--glucuronide (M1), raloxifene-4'--glucuronide (M2), and raloxifene-6,4'-diglucuronide (M3). Caco-2 cell monolayer experiments indicated an interaction of raloxifene with Pgp. The ATPase assay confirmed the raloxifene interaction with Pgp and indicated interactions of all raloxifene species with MRP1, MRP2, MRP3, and breast cancer resistance protein, except for M1, which did not show any interactions with MRP2. Furthermore, the vesicular experiments confirmed the interaction of M2 and M3 with MRP2. Although the in vivo study on osteoporotic postmenopausal women on raloxifene could not confirm a significant influence of ABCB1 and ABCC2 genetic polymorphisms on its pharmacokinetics, a clear trend toward higher total raloxifene concentrations was observed in carriers of at least 1 ABCB1 c.3435T allele. Moreover, the same polymorphism effect was also observed as a significant increase in total hip bone mineral density after 1 year of treatment. The results of our study support the involvement of efflux transporters in disposition of raloxifene and its metabolites and may partially explain the observed raloxifene variability by the influence of the ABCB1 c.3435C>T polymorphism. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 2 AbstractRaloxifene exhibits quite a large and unexplained interindividual variability in its pharmacokinetics and pharmacodynamics. The aim of our study was to identify transporters involved in the efflux of raloxifene and its glucuronide metabolites by various in vitro models and by an in vivo study to explore the possible involvement of Pgp, MRP1, MRP2, MRP3, and BCRP in the observed high interindividual variability. Experiments with PAMPA (Parallel Artificial Membrane Permeability Assay) showed the highest passive permeability for raloxifene, followed by raloxifene-6-β-glucuronide (M1), raloxifene-4'-β-glucuronide (M2) and raloxifene-6,4'-diglucuronide (M3). Caco-2 cell monolayer experiments indicated an inte...
BackgroundRaloxifene, a selective estrogen receptor modulator, exhibits quite large and unexplained interindividual variability in pharmacokinetics and pharmacodynamics. The aim of this study was to determine the role of organic-anion transporting polypeptides OATP1B1 and OATP1B3 and their genetic variants in the pharmacokinetics and pharmacodynamics of raloxifene.MethodsTo test the role of OATP1B1 and OATP1B3 transporters on hepatic uptake of raloxifene and its metabolites an in vitro model of Chinese Hamster Ovary cells expressing OATP1B1 or OATP1B3 was employed. The influence of OATP1B1 and OATP1B3 genetic variants on in vivo pharmacokinetics and pharmacodynamics was evaluated in 53 osteoporotic postmenopausal women treated with raloxifene.ResultsOur in vitro results showed that raloxifene and two of the three metabolites, raloxifene-4'-β-glucuronide (M2) and raloxifene-6,4'-diglucuronide (M3), interact with OATP1B1 and OATP1B3. Higher M3 and total raloxifene serum concentrations in patients correlated with lower serum levels of bone resorption marker, serum C-terminal telopeptide fragments of type I collagen, indicating a higher antiresorptive effect of raloxifene. Higher concentrations of M2 correlated with higher increase of lumbar spine bone mineral density supporting the raloxifene vertebral fracture specific protection effect. Finally, raloxifene, M3 and total raloxifene serum concentrations were significantly higher in patients with SLCO1B1 c.388A > G polymorphism and *1b haplotype implicating a considerable genetic effect on pharmacokinetics and pharmacodynamics of raloxifene.ConclusionsThese findings indicate that SLCO1B1 c.388A > G polymorphism could play an important role in pharmacokinetics and pharmacodynamics of raloxifene.
Background: Our study was designed to determine bone mineral density (BMD) in patients beginning hemodialysis (HD) treatment, a possible correlation with the duration of renal failure prior to treatment, a possible correlation with the basic disease and the association with the concentration of intact parathormone (iPTH). Methods: Our prospective clinical trial included 50 patients beginning HD treatment. Cortical bone mineral density (BMDc) was measured at the left femoral neck and trabecular bone mineral density (BMDt) in the region of the lumbosacral spine. Bone mineral density (BMD) was measured by quantitative digital radiography using a Hologic 2000 plus device belonging to the third generation of densitometers based on dual-energy X-ray absorptiometry. Results: In patients (PTS) beginning HD, the average BMDc was 82 ± 15% of BMDc in a healthy population of corresponding age and sex. The average BMDt was 91 ± 16% of BMDt in a healthy population of corresponding age and sex. The difference was statistically significant (p < 0.05). There is a negative correlation between iPTH and BMDc r = –0.34 (p < 0.02). Patients with chronic glomerulonephritis (GN) had a statistically significantly higher BMDc (g/cm2) (p < 0.01) than those with analgetic nephropathy (AN). PTS with AN have lower BMDc (g/cm2, %) (p < 0.02) and BMDt (p < 0.005) than the rest of the PTS, iPTH in PTS with AN is higher than in the rest of the PTS (p < 0.05). Conclusions: In PTS at the beginning of HD, BMD is lower than in healthy people of corresponding age and sex. This means that BMD already decreases prior to HD. BMDc was statistically significantly lower than BMDt (p < 0.00005). PTS with AN have lower BMD than those with GN and all remaining PTS. A negative correlation between iPTH and BMDc was found.
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