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tacrolimus and polymorphism

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https://www.readbyqxmd.com/read/29329489/mycophenolic-acid-and-its-metabolites-in-kidney-transplant-recipients-a-semimechanistic-enterohepatic-circulation-model-to-improve-estimating-exposure
#1
Malek Okour, Pamala A Jacobson, Mariam A Ahmed, Ajay K Israni, Richard C Brundage
Mycophenolic acid (MPA) is an approved immunosuppressive agent widely prescribed to prevent rejection after kidney transplantation. Wide between-subject variability (BSV) in MPA exposure exists which in part may be due to variability in enterohepatic recirculation (EHC). Several modeling strategies were developed to evaluate EHC as part of MPA pharmacokinetics, however mechanistic representation of EHC is limited. These models have not provided a satisfactory representation of the physiology of EHC in their modeling assumptions...
January 12, 2018: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29279557/effectiveness-of-measuring-genetic-polymorphisms-in-metabolizing-enzymes-of-tacrolimus-within-one-medical-facility
#2
Tomohiro Kaneko, Momoko Arai, Atsushi Watanabe, Shuichi Tsuruoka
OBJECTIVES: Because genetic polymorphisms cause diverse activity in drug metabolizing enzymes, drug concentrations in the blood may be variable among patients. We analyzed the genotypes of CYP3A5 and MDR1, and investigated their relationship with whole blood drug concentrations. METHODS: Eight patients were administered an oral dose of tacrolimus for one week or longer prior to enrollment in this study. Whole blood concentrations for tacrolimus were measured 12 hours post oral administration, on the same day as genotyping, within our hospital using a fully automated gene analyzer...
2017: Journal of Nippon Medical School, Nippon Ika Daigaku Zasshi
https://www.readbyqxmd.com/read/29229354/comparative-clinical-trial-of-the-variability-factors-of-the-exposure-indices-used-for-the-drug-monitoring-of-two-tacrolimus-formulations-in-kidney-transplant-recipients
#3
Pierre Marquet, Laetitia Albano, Jean-Baptiste Woillard, Lionel Rostaing, Nassim Kamar, Charlotte Sakarovitch, Philippe Gatault, Matthias Buchler, Bernard Charpentier, Eric Thervet, Elisabeth Cassuto
BACKGROUND: Several studies found differences in tacrolimus whole blood trough levels (C0) or area-under-the curve (AUC) between the twice-daily (Tac-BID) and once-daily (Tac-OD) formulations given to kidney transplant recipients at equal doses. As C0 is widely used as a surrogate of the AUC for individual dose adjustment, this study investigated the correlation and proportionality between C0 and the 24h-AUC, depending on the formulation, time post-transplantation, pharmacogenetics traits and other individual characteristics...
December 8, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/29199543/genetic-variations-of-the-xenoreceptors-nr1i2-and-nr1i3-and-their-effect-on-drug-disposition-and-response-variability
#4
Litaty Céphanoée Mbatchi, Jean-Paul Brouillet, Alexandre Evrard
NR1I2 (PXR) and NR1I3 (CAR) are nuclear receptors that are classified as xenoreceptors. Upon activation by various xenobiotics, including marketed drugs, they regulate the transcription level of major drug-metabolizing enzymes and transporters and facilitate the elimination of xenobiotics from the body. The modulation of the activity of these two xenoreceptors by various ligands is a major source of pharmacokinetic variability of environmental origin. NR1I2 and NR1I3 genetic polymorphisms can affect the pharmacokinetics and therapeutic response to many drugs, such as irinotecan, tacrolimus and atazanavir...
December 4, 2017: Pharmacogenomics
https://www.readbyqxmd.com/read/29162334/results-of-asertaa-a-randomized-prospective-crossover-pharmacogenetic-study-of-immediate-release-versus-extended-release-tacrolimus-in-african-american-kidney-transplant-recipients
#5
Jennifer Trofe-Clark, Daniel C Brennan, Patricia West-Thielke, Michael C Milone, Mary Ann Lim, Robin Neubauer, Vincenza Nigro, Roy D Bloom
BACKGROUND: Differences in tacrolimus dosing across ancestries is partly attributable to polymorphisms in CYP3A5 genes that encode tacrolimus-metabolizing cytochrome P450 3A5 enzymes. The CYP3A5*1 allele, preponderant in African Americans, is associated with rapid metabolism, subtherapeutic concentrations, and higher dose requirements for tacrolimus, all contributing to worse outcomes. Little is known about the relationship between CYP3A5 genotype and the tacrolimus pharmacokinetic area under the curve (AUC) profile in African Americans or whether pharmacogenetic differences exist between conventional twice-daily, rapidly absorbed, immediate-release tacrolimus (IR-Tac) and once-daily extended-release tacrolimus (LifeCycle Pharma Tac [LCPT]) with a delayed absorption profile...
November 18, 2017: American Journal of Kidney Diseases: the Official Journal of the National Kidney Foundation
https://www.readbyqxmd.com/read/29161757/impact-of-cyp3a5-genomic-variances-on-clinical-outcomes-among-african-american-kidney-transplant-recipients
#6
Tomefa E Asempa, Lorita M Rebellato, Suzanne Hudson, Kimberly Briley, Angela Q Maldonado
Little is known about the impact of CYP3A5 polymorphisms on transplantation outcomes among African-American (AA) kidney transplant recipients. To assess this issue, clinical outcomes were compared between AA CYP3A5*1 expressers versus non-expressers. This retrospective cohort study analyzed AA kidney transplant recipients. Biopsy-proven acute rejection (BPAR), delayed graft function (DGF), glomerular filtration rate (GFR), infections and tacrolimus dosing requirements were examined in 106 immunologically high-risk AA kidney transplant patients over a 2 year follow-up period...
November 21, 2017: Clinical Transplantation
https://www.readbyqxmd.com/read/29113387/tacrolimus-dose-requirement-based-on-the-cyp3a5-genotype-in-renal-transplant-patients
#7
Lihui Qu, Yingying Lu, Meike Ying, Bingjue Li, Chunhua Weng, Zhoutao Xie, Ludan Liang, Chuan Lin, Xian Yang, Shi Feng, Yucheng Wang, Xiujin Shen, Qin Zhou, Ying Chen, Zhimin Chen, Jianyong Wu, Weiqiang Lin, Yi Shen, Jing Qin, Hang Xu, Feng Xu, Junwen Wang, Jianghua Chen, Hong Jiang, Hongfeng Huang
Tacrolimus (FK506) and cyclosporine A (CsA) are widely used to protect graft function after renal transplantation. The aim of the present study is to determine whether the single nucleotide polymorphism of CYP3A5 is a predictive index of FK506 dose requirement, and also the selection yardstick of FK506 or CsA treatment.We tested archival peripheral blood of 218 kidney recipients for CYP3A5 genotyping with PCR-SSP. Meanwhile, the dose of FK506 and CsA was recorded, blood concentration of the drugs was measured, and graft outcome was monitored...
October 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/29054923/activity-of-the-calcineurin-pathway-in-patients-on-the-liver-transplantation-waiting-list-factors-of-variability-and-response-to-tacrolimus-inhibition
#8
Ofelia Noceti, Lucie Pouché, Patricia Esperón, Daniela Lens, Marcelo Vital, Cristina Touriño, Solange Gerona, Jean Baptiste Woillard, Pierre Marquet
BACKGROUND: We sought to evaluate, in patients on a liver transplantation waiting list, potential biomarkers of the base calcineurin pathway activity with use of a new model of nonstimulated peripheral blood mononuclear cells (PBMC) and ex vivo response to tacrolimus (TAC). METHODS: The calcineurin pathway activity was explored ex vivo in stimulated and nonstimulated PBMC from 19 patients. The inhibition of NFATC1(+) translocation to PBMC, expression of intracellular IL-2, and membrane CD25 in different T-cell subsets were measured by multiparametric flow cytometry before and after exposure to TAC...
October 20, 2017: Clinical Chemistry
https://www.readbyqxmd.com/read/28945481/long-term-influence-of-cyp3a5-cyp3a4-abcb1-and-nr1i2-polymorphisms-on-tacrolimus-concentration-in-chinese-renal-transplant-recipients
#9
Fei Liu, Yang-Meng Ou, Ai-Rong Yu, Lei Xiong, Hua-Wen Xin
BACKGROUND: The highly pharmacokinetic variability of tacrolimus makes it difficult to adjust the dose. In the current study, we investigated the influence of gene polymorphisms and other clinical factors on long-term tacrolimus dosing in Chinese renal transplant recipients. METHODS: A total of 276 renal transplant recipients were enrolled. The tacrolimus trough concentration and other clinical variables were recorded for 5 years following transplantation. Eight single nucleotide polymorphisms in four genes (CYP3A5, CYP3A4, ABCB1, and NR1I2) were genotyped using polymerase chain reaction-restriction fragment length polymorphism analysis and sequencing...
September 25, 2017: Genetic Testing and Molecular Biomarkers
https://www.readbyqxmd.com/read/28941036/association-of-donor-sumo4-rs237025-genetic-variant-with-tacrolimus-elimination-in-the-early-period-after-liver-transplantation
#10
Tao Zhang, Yuan Liu, Rong Zeng, Qi Ling, Peihao Wen, Junwei Fan, Zhihai Peng
BACKGROUNDS & AIMS: Individualized tacrolimus treatment can improve drug safety and efficacy. In this study, we aimed to investigate the association of donor and recipient small ubiquitin-like modifier 4 (SUMO4) rs237025 polymorphisms with tacrolimus elimination and the potential mechanism. METHODS: A total of 297 liver transplant patients were enrolled in the study. CYP3A5 rs776746 and SUMO4 rs237025 were genotyped using TaqMan SNPs assays. The activity of nuclear factor-kB (NF-kB) was evaluated by luciferase assay...
September 21, 2017: Liver International: Official Journal of the International Association for the Study of the Liver
https://www.readbyqxmd.com/read/28891077/a-comparison-of-the-effects-of-cyp3a5-polymorphism-on-tacrolimus-blood-concentrations-measured-by-4-immunoassay-methods-in-renal-transplant-patients
#11
Yumiko Akamine, Hideaki Kagaya, Tadashi Ohkubo, Shigeru Satoh, Masatomo Miura
WHAT IS KNOWN AND OBJECTIVE: The anti-tacrolimus antibodies used in commercial immunoassay methods have cross-reactivity with tacrolimus metabolites. The aim of this study was to investigate differences in the effects of CYP3A5 polymorphism on tacrolimus concentrations obtained by four immunoassay methods in renal transplant patients. METHODS: Samples (n = 508) were evaluated using four immunoassays (chemiluminescence enzyme immunoassay [CLIA], affinity column-mediated immunoassay [ACMIA], electrochemiluminescence immunoassay [ECLIA] and latex agglutination turbidimetric immunoassay [LTIA])...
September 10, 2017: Journal of Clinical Pharmacy and Therapeutics
https://www.readbyqxmd.com/read/28833329/population-pharmacokinetics-and-bayesian-estimation-of-tacrolimus-exposure-in-chinese-liver-transplant-patients
#12
B Chen, H-Q Shi, X-X Liu, W-X Zhang, J-Q Lu, B-M Xu, H Chen
WHAT IS KNOWN AND OBJECTIVES: Tacrolimus (TAC) is widely used as part of immunosuppressive regimens. There is great interindividual variation on the disposition of TAC. The aim of this study was to develop a population pharmacokinetic (PPK) model for Chinese liver transplant patients and evaluate genetic polymorphism and other possible factors on the PK parameters. The exposure of TAC is to be estimated through Bayesian modelling. METHODS: A total of 47 sets of rich-time PK and 1234 conventional therapeutic drug monitoring (TDM) data were collected from 125 Chinese liver transplant patients...
August 17, 2017: Journal of Clinical Pharmacy and Therapeutics
https://www.readbyqxmd.com/read/28805561/kcnj11-and-kcnq1-gene-polymorphisms-are-not-associated-with-post-transplant-diabetes-mellitus-in-kidney-allograft-recipients-treated-with-tacrolimus
#13
E Dabrowska-Zamojcin, M Tarnowski, M Szydlowski, M Romanowski, V Dziedziejko, K Safranow, L Domanski, A Pawlik
Post-transplant diabetes mellitus (PTDM) is a metabolic disorder occurring after solid organ transplantation during the therapy with calcineurin inhibitors. ATP-sensitive potassium channels KCNJ11 and KCNQ1 play an important role in the regulation of insulin secretion by β cells and development of diabetes mellitus. Numerous studies have confirmed the association between KCNJ11 and KCNQ1 gene polymorphisms and type 2 diabetes. The aim of this study was to examine the association between KCNJ11 and KCNQ1 gene polymorphisms and posttransplant diabetes mellitus in kidney allograft recipients treated with tacrolimus...
2017: Folia Biologica (Praha)
https://www.readbyqxmd.com/read/28777242/analysis-of-common-polymorphisms-within-nr1i2-and-nr1i3-genes-and-tacrolimus-dose-adjusted-concentration-in-stable-kidney-transplant-recipients
#14
Mateusz Kurzawski, Damian Malinowski, Krzysztof Dziewanowski, Marek Droździk
OBJECTIVES: Several genetic factors were identified to be responsible for interidividual variability in tacrolimus (TAC) pharmacokinetics, with the predominant role of CYP3A5 and CYP3A4 polymorphisms. In this study, genetic variants of NR1I2 and NR1I3 nuclear receptors (responsible for the regulation of drug-metabolizing enzymes and transporters at the transcriptional level) were evaluated for their potential association with altered TAC concentrations. MATERIALS AND METHODS: Two hundred and forty White kidney transplant patients were genotyped for five single-nucleotide polymorphisms (rs3814055, rs6785049, rs2276707, rs2307424, and rs2307418) in NR1I2 and NR1I3 genes...
October 2017: Pharmacogenetics and Genomics
https://www.readbyqxmd.com/read/28736028/association-between-tacrolimus-pharmacokinetics-and-cytochrome-p450-3a5-and-multidrug-resistance-protein-1-exon-21-polymorphisms
#15
M Soda, M Fujitani, R Michiuchi, A Shibayama, K Kanamori, S Yoshikuni, Y Ohno, T Tsuchiya, A Suzuki, K Horie, T Deguchi, Y Itoh, K Kitaichi
BACKGROUND: Individual differences in the pharmacokinetics (PK) of tacrolimus (TAC), an immunosuppressive drug, are reportedly associated with single-nucleotide polymorphisms (SNPs) of cytochrome P450 (CYP) 3A5 and multidrug resistance protein 1 (MDR1). We determined the effect of SNPs in CYP3A5 and MDR1 exons 21 and 26 on TAC PK parameters. METHODS: Thirty-eight Japanese patients who underwent renal transplantation were genotyped for CYP3A5 and exons 21 and 26 of MDR1 with the use of polymerase chain reaction-restriction fragment length polymorphism analysis...
July 2017: Transplantation Proceedings
https://www.readbyqxmd.com/read/28717926/clinical-evaluation-of-modified-release-and-immediate-release-tacrolimus-formulations
#16
Simon Tremblay, Rita R Alloway
The science of drug delivery has evolved considerably and has led to the development of multiple sustained release formulations. Each of these formulations can present particular challenges in terms of clinical evaluation and necessitate careful study to identify their optimal use in practice. Tacrolimus is an immunosuppressive agent that is widely used in organ transplant recipients. However, it is poorly soluble, has an unpredictable pharmacokinetic profile subject to important genetic polymorphisms and drug-drug interactions, and has a narrow therapeutic index...
July 17, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28704257/the-combination-of-cyp3a4-22-and-cyp3a5-3-single-nucleotide-polymorphisms-determines-tacrolimus-dose-requirement-after-kidney-transplantation
#17
Nuria Lloberas, Laure Elens, Ines Llaudó, Ariadna Padullés, Teun van Gelder, Dennis A Hesselink, Helena Colom, Franc Andreu, Joan Torras, Oriol Bestard, Josep M Cruzado, Salvador Gil-Vernet, Ron van Schaik, Josep M Grinyó
INTRODUCTION: Tacrolimus (Tac) has a narrow therapeutic window and shows large between-patient pharmacokinetic variability. As a result, over-immunosuppression and under-immunosuppression are frequently encountered in daily clinical practice. Unraveling the impact of genetic polymorphisms on Tac pharmacokinetics may help to refine therapy. In this study, the associations of single-nucleotide polymorphisms (SNPs) in drug-metabolizing enzymes (CYP3A) with Tac pharmacokinetics were investigated in renal transplant recipients...
September 2017: Pharmacogenetics and Genomics
https://www.readbyqxmd.com/read/28689037/association-of-donor-and-recipient-sumo4-rs237025-genetic-variant-with-new-onset-diabetes-mellitus-after-liver-transplantation-in-a-chinese-population
#18
Tao Zhang, Yuan Liu, Yibo Hu, Xiaoqing Zhang, Lin Zhong, Junwei Fan, Zhihai Peng
BACKGROUNDS & AIMS: New-onset diabetes mellitus (NODM) is a common complication after liver transplantation (LT). The small ubiquitin-like modifier 4 (SUMO4) rs237025 polymorphism has been reported to be associated with type 2 diabetes mellitus (T2DM). In this study, we aimed to evaluate the association of donor and recipient SUMO4 rs237025 polymorphisms with NODM and the long-term consequences of NODM after LT. METHODS: A total of 126 liver transplant patients were enrolled in the study...
September 5, 2017: Gene
https://www.readbyqxmd.com/read/28685716/gene-variations-of-sixth-complement-component-affecting-tacrolimus-metabolism-in-patients-with-liver-transplantation-for-hepatocellular-carcinoma
#19
Jian-Hua Liao, Chang-Can Li, Shao-Han Wu, Jun-Wei Fan, Hai-Tao Gu, Zhao-Wen Wang
BACKGROUND: Orthotopic liver transplantation (OLT) improves the prognosis of patients with hepatocellular carcinoma (HCC). Moreover, the complement system is a powerful immune effector that can affect liver function and process of liver cirrhosis. However, studies correlating the complement system with tacrolimus metabolism after OLT are scarce. In this study, the role of single nucleotide polymorphisms (SNPs) associated with the sixth complement component (C6) in tacrolimus metabolism was investigated during the early stages of liver transplantation...
July 20, 2017: Chinese Medical Journal
https://www.readbyqxmd.com/read/28655393/the-role-of-single-nucleotide-polymorphisms-of-cyp3a-and-abcb1-on-tacrolimus-predose-concentration-in-kidney-transplant-recipients
#20
Gregor Mlinšek, Vita Dolžan, Katja Goričar, Jadranka Buturović-Ponikvar, Miha Arnol
BACKGROUND: Tacrolimus has a narrow therapeutic drug window but high inter- and intrapatient variability. Our aim is to construct a model able to predict optimal maintenance tacrolimus predose concentration (C<sub>0</sub>) in kidney transplant patients. Here we present our study design and genotype and variant allele frequencies for the selected single nucleotide polymorphisms of genes involved in tacrolimus metabolism in our national cohort of kidney transplant recipients...
2017: Clinical Nephrology
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