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      Impact ofUGT2B17Gene Deletion on the Pharmacokinetics of 17-Hydroexemestane in Healthy Volunteers

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          Abstract

          <p class="first" id="P1">Exemestane is an aromatase inhibitor drug used for the treatment of hormone-dependent breast cancer. 17-hydroexemestane, the major and biologically active metabolite of exemestane in humans is eliminated via glucuronidation by the polymorphic <i>UGT2B17</i> phase II drug metabolizing enzyme. Previous microsomal studies have shown that <i>UGT2B17</i> gene deletion affects the intrinsic hepatic clearances of 17-hydroexemestane <i>in vitro.</i> In this open-label study, we set out to assess the effect of <i>UGT2B17</i> gene deletion on the pharmacokinetics of 17-hydroexemestane in healthy female volunteers with and without <i>UGT2B17</i>. To achieve this goal, 14 healthy postmenopausal women (eight carriers of the homozygous <i>UGT2B17</i> wild-type allele and six carriers of the homozygous <i>UGT2B17</i> gene deletion allele) were enrolled and invited to receive a single 25 mg oral dose of exemestane. Pharmacokinetics was assessed over 72 hours post-dosing. Our results showed that there were statistically significant differences in plasma 17-hydroexemestane AUC <sub>0-∞</sub> ( <i>p</i> = 0.0007) and urine 17-hydroexemestane C <sub>24hr</sub> ( <i>p</i> = 0.001) between <i>UGT2B17</i> genotype groups. Our data suggest that <i>UGT2B17</i> gene deletion influences 17-hydroexemestane pharmacokinetics in humans. </p>

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          Most cited references28

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          Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial.

          Early improvements in disease-free survival have been noted when an aromatase inhibitor is given either instead of or sequentially after tamoxifen in postmenopausal women with oestrogen-receptor-positive early breast cancer. However, little information exists on the long-term effects of aromatase inhibitors after treatment, and whether these early improvements lead to real gains in survival. 4724 postmenopausal patients with unilateral invasive, oestrogen-receptor-positive or oestrogen-receptor-unknown breast cancer who were disease-free on 2-3 years of tamoxifen, were randomly assigned to switch to exemestane (n=2352) or to continue tamoxifen (n=2372) for the remainder of a 5-year endocrine treatment period. The primary endpoint was disease-free survival; overall survival was a secondary endpoint. Efficacy analyses were intention-to-treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN11883920. After a median follow-up of 55.7 months (range 0-89.7), 809 events contributing to the analysis of disease-free survival had been reported (354 exemestane, 455 tamoxifen); unadjusted hazard ratio 0.76 (95% CI 0.66-0.88, p=0.0001) in favour of exemestane, absolute benefit 3.3% (95% CI 1.6-4.9) by end of treatment (ie, 2.5 years after randomisation). 222 deaths occurred in the exemestane group compared with 261 deaths in the tamoxifen group; unadjusted hazard ratio 0.85 (95% CI 0.71-1.02, p=0.08), 0.83 (0.69-1.00, p=0.05) when 122 patients with oestrogen-receptor-negative disease were excluded. Our results suggest that early improvements in disease-free survival noted in patients who switch to exemestane after 2-3 years on tamoxifen persist after treatment, and translate into a modest improvement in overall survival.
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            Genome-wide copy-number-variation study identified a susceptibility gene, UGT2B17, for osteoporosis.

            Osteoporosis, a highly heritable disease, is characterized mainly by low bone-mineral density (BMD), poor bone geometry, and/or osteoporotic fractures (OF). Copy-number variation (CNV) has been shown to be associated with complex human diseases. The contribution of CNV to osteoporosis has not been determined yet. We conducted case-control genome-wide CNV analyses, using the Affymetrix 500K Array Set, in 700 elderly Chinese individuals comprising 350 cases with homogeneous hip OF and 350 matched controls. We constructed a genomic map containing 727 CNV regions in Chinese individuals. We found that CNV 4q13.2 was strongly associated with OF (p = 2.0 x 10(-4), Bonferroni-corrected p = 0.02, odds ratio = 1.73). Validation experiments using PCR and electrophoresis, as well as real-time PCR, further identified a deletion variant of UGT2B17 in CNV 4q13.2. Importantly, the association between CNV of UGT2B17 and OF was successfully replicated in an independent Chinese sample containing 399 cases with hip OF and 400 controls. We further examined this CNV's relevance to major risk factors for OF (i.e., hip BMD and femoral-neck bone geometry) in both Chinese (689 subjects) and white (1000 subjects) samples and found consistently significant results (p = 5.0 x 10(-4) -0.021). Because UGT2B17 encodes an enzyme catabolizing steroid hormones, we measured the concentrations of serum testosterone and estradiol for 236 young Chinese males and assessed their UGT2B17 copy number. Subjects without UGT2B17 had significantly higher concentrations of testosterone and estradiol. Our findings suggest the important contribution of CNV of UGT2B17 to the pathogenesis of osteoporosis.
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              Exemestane versus anastrozole in postmenopausal women with early breast cancer: NCIC CTG MA.27--a randomized controlled phase III trial.

              In patients with hormone-dependent postmenopausal breast cancer, standard adjuvant therapy involves 5 years of the nonsteroidal aromatase inhibitors anastrozole and letrozole. The steroidal inhibitor exemestane is partially non-cross-resistant with nonsteroidal aromatase inhibitors and is a mild androgen and could prove superior to anastrozole regarding efficacy and toxicity, specifically with less bone loss.
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                Author and article information

                Journal
                The Journal of Clinical Pharmacology
                The Journal of Clinical Pharmacology
                Wiley
                00912700
                July 2016
                July 2016
                December 31 2015
                : 56
                : 7
                : 875-884
                Affiliations
                [1 ]Harding University College of Pharmacy; Searcy; AR USA
                [2 ]University of Pikeville; Kentucky College of Osteopathic Medicine; Pikeville KY USA
                [3 ]Harding University Physician Assistant Program; Searcy; AR USA
                [4 ]University of Arkansas for Medical Sciences; College of Pharmacy; Little Rock AR USA
                Article
                10.1002/jcph.673
                4882280
                26608382
                60972f7d-1d0c-44ca-b185-02b2daafd6b3
                © 2015

                http://doi.wiley.com/10.1002/tdm_license_1.1

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