Browsing by Subject "mycophenolic acid"

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    1-Alpha, 25-dihydroxyvitamin D3 alters the pharmacokinetics of mycophenolic acid in renal transplant recipients by regulating two extrahepatic UDP-glucuronosyltransferases 1A8 and 1A10
    (Elsevier, 2016-12) Wang, Xiaoliang; Wang, Hongwei; Shen, Bing; Overholser, Brian R.; Cooper, Bruce R.; Lu, Yinghao; Tang, Huamei; Zhou, Chongzhi; Sun, Xing; Zhong, Lin; Favus, Murray J.; Decker, Brian S.; Liu, Wanqing; Peng, Zhihai; Department of Medicine, IU School of Medicine
    Mycophenolic acid (MPA) is an important immunosuppressant broadly used in renal transplantation. However, the large inter-patient variability in mycophenolic acid (MPA) pharmacokinetics (PK) limits its use. We hypothesize that extrahepatic metabolism of MPA may have significant impact on MPA PK variability. Two intestinal UDP-glucuronosyltransferases 1A8 and 1A10 plays critical role in MPA metabolism. Both in silico and previous genome-wide analyses suggested that vitamin D (VD) may regulate intestinal UGT1A expression. We validated the VD response elements (VDREs) across the UGT1A locus with chromatin immunoprecipitation (ChIP) and luciferase reporter assays. The impact of 1-alpha,25-dihydroxyvitamin D3 (D3) on UGT1A8 and UGT1A10 transcription and on MPA glucuronidation was tested in human intestinal cell lines LS180, Caco-2 and HCT-116. The correlation between transcription levels of VD receptor (VDR) and the two UGT genes were examined in human normal colorectal tissue samples (n = 73). PK alterations of MPA following the parent drug, mycophenolate mofetil (MMF), and D3 treatment was assessed among renal transplant recipients (n = 10). Our ChIP assay validate three VDREs which were further demonstrated as transcriptional enhancers with the luciferase assays. D3 treatment significantly increased transcription of both UGT genes as well as MPA glucuronidation in cells. The VDR mRNA level was highly correlated with that of both UGT1A8 and UGT1A10 in human colorectal tissue. D3 treatment in patients led to about 40% reduction in both AUC0-12 and Cmax while over 70% elevation of total clearance of MPA. Our study suggested a significant regulatory role of VD on MPA metabolism and PK via modulating extrahepatic UGT activity.
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    Pharmacokinetic Variability of Mycophenolic Acid in Pediatric and Adult Patients with Hematopoietic Stem Cell Transplantation
    (Wiley, 2016-11) Zhang, Daping; Renbarger, Jamie L.; Chow, Diana S-L.; Department of Pediatrics, IU School of Medicine
    The aim of this study was to evaluate the pharmacokinetic variations of mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), in both pediatric and adult patients following hematopoietic stem cell transplantation (HSCT). Twenty pediatric patients with a median age of 3 years (range 0.2-12 years) and 13 adult patients with a median age of 54 years (range 18-63 years) were enrolled. Blood samples were collected on days 0, 7, 14, 21, and 30 after allogeneic HSCT. Total and free (unbound) MPA as well as MPA 7-O-glucuronide (MPAG) were quantified using a validated LC-MS/MS assay. The plasma protein binding of MPA and MPAG did not change significantly in pediatric patients over the 1-month sampling period post-HSCT. However, it increased in adult patients from day 7 to day 30 post-HSCT, from 97.3 ± 0.8% to 98.3 ± 0.6% for MPA (P < .05), and 74.6 ± 9.4% to 82.9 ± 8.1% for MPAG (P < .05). The plasma protein binding of MPA was significantly higher in males compared to females in both pediatric (98.3 ± 1.1% vs 97.4 ± 1.1%) and adult (98.1 ± 0.7% vs 97.4 ± 1.2%) patients (P < .05). The MPAG/MPA ratios on a milligram-per-kilogram dose basis in adult patients were significantly higher than those in pediatric patients (4.3 ± 3.4 vs 2.4 ± 2.6; P < .05). Time-dependent plasma protein binding and age-related differences in MPA metabolism at least in part impact the reported large intra- and interindividual variability in MPA pharmacokinetics. These patient and pharmacologic factors, if incorporated into MMF regimen design and modification, may contribute to the rational dose selection of MMF in HSCT patients.