title: 1-Alpha, 25-dihydroxyvitamin D3 alters the pharmacokinetics of mycophenolic acid in renal transplant recipients by regulating two extrahepatic UDP-glucuronosyltransferases 1A8 and 1A10.
abstract: 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 AUC0-12and 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.
authors: Department of General Surgery, Shanghai First People's Hospital, Medical College, Shanghai Jiaotong University, Shanghai, P. R. China; Department of Medicinal Chemistry & Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Ind, USA.
authors: Xiaoliang
authors: X
authors: Wang
authors: Section of Endocrinology, Department of Medicine, The University of Chicago, Chicago, Ill, USA.
authors: Hongwei
authors: H
authors: Wang
authors: Department of Urology, Shanghai First People's Hospital, Medical College, Shanghai Jiaotong University, Shanghai, P. R. China.
authors: Bing
authors: B
authors: Shen
authors: Department of Pharmacy Practice, College of Pharmacy, Purdue University, West Lafayette, Ind, USA.
authors: Brian R
authors: BR
authors: Overholser
authors: Bindley Bioscience Center, Metabolite Profiling Facility, Purdue University, West Lafayette, Ind, USA.
authors: Bruce R
authors: BR
authors: Cooper
authors: Department of Hematology, Affiliated Hospital of Guiyang Medical College, The Hematopoietic Stem Cell Transplant Center of Guizhou Province, Guiyang, P. R. China.
authors: Yinghao
authors: Y
authors: Lu
authors: Department of Pathology, Shanghai First People's Hospital, Medical College, Shanghai Jiaotong University, Shanghai, P. R. China.
authors: Huamei
authors: H
authors: Tang
authors: Department of General Surgery, Shanghai First People's Hospital, Medical College, Shanghai Jiaotong University, Shanghai, P. R. China.
authors: Chongzhi
authors: C
authors: Zhou
authors: Department of General Surgery, Shanghai First People's Hospital, Medical College, Shanghai Jiaotong University, Shanghai, P. R. China.
authors: Xing
authors: X
authors: Sun
authors: Department of General Surgery, Shanghai First People's Hospital, Medical College, Shanghai Jiaotong University, Shanghai, P. R. China.
authors: Lin
authors: L
authors: Zhong
authors: Section of Endocrinology, Department of Medicine, The University of Chicago, Chicago, Ill, USA.
authors: Murray J
authors: MJ
authors: Favus
authors: Division of Nephrology, School of Medicine, Indiana University, Indianapolis, Ind, USA; Department of Medicine, School of Medicine, Indiana University, Indianapolis, Ind, USA.
authors: Brian S
authors: BS
authors: Decker
authors: Department of Medicinal Chemistry & Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Ind, USA. Electronic address: liu781@purdue.edu.
authors: Wanqing
authors: W
authors: Liu
authors: Department of General Surgery, Shanghai First People's Hospital, Medical College, Shanghai Jiaotong University, Shanghai, P. R. China. Electronic address: pengzhihai@sjtu.edu.cn.
authors: Zhihai
authors: Z
authors: Peng
mesh_terms: D018938:Caco-2 Cells; D047369:Chromatin Immunoprecipitation; D003001:Cloning, Molecular; D003106:Colon / Q000187:drug effects / Q000201:enzymology; D005786:Gene Expression Regulation / Q000187:drug effects; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D016030:Kidney Transplantation; D008099:Liver / Q000378:metabolism*; D008156:Luciferases / Q000378:metabolism; D009173:Mycophenolic Acid / Q000493:pharmacokinetics* / Q000494:pharmacology; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism; D012007:Rectum / Q000187:drug effects / Q000201:enzymology; D015203:Reproducibility of Results; D020218:Response Elements / Q000235:genetics; D014158:Transcription, Genetic; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D020719:Glucuronides; D018167:Receptors, Calcitriol; C118756:dihydroxy-vitamin D3; D014807:Vitamin D; D008156:Luciferases; C476725:bilirubin uridine-diphosphoglucuronosyl transferase 1A10; D014453:Glucuronosyltransferase; C454320:UDP-glucuronosyltransferase, UGT1A8; D009173:Mycophenolic Acid