Associations of UDP-glucuronosyltransferases polymorphisms with mycophenolate mofetil pharmacokinetics in Chinese renal transplant patients

Xie, Xiao-chun; Li, Jun; Wang, Hongyang; Li, Hongliang; Liu, Jing; Fu, Qian; Huang, Jiawen; Zhu, Chunrong; Zhong, Guoping; Wang, Xueding; Sun, Pingping; Huang, Min; Wang, Changxi; Li, Jiali

doi:10.1038/aps.2015.7

Cited by 32 publications

(26 citation statements)

References 34 publications

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“…It was demonstrated that the opioid binding site in UGT2B7 is within the first 119 amino-terminal amino acids (N-terminal half of the protein) [61] . Polymorphisms in UGT2B7 showed significant association with MPA AUC in previously reported studies [62][63][64] . In our study, the UGT2B7 211G>T genotype was found to be an important factor that contributes to the variability in MPA pharmacokinetics.…”

Section: Discussionsupporting

confidence: 53%

Population pharmacokinetics and Bayesian estimation of mycophenolic acid concentrations in Chinese adult renal transplant recipients

Zhou

Wang

et al. 2017

Acta Pharmacol Sin

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Mycophenolate mofetil (MMF) is an important immunosuppressant used in renal transplantation, and mycophenolic acid (MPA) is the active component released from the ester prodrug MMF. The objective of this study was to investigate the population pharmacokinetics of mycophenolic acid (MPA) following oral administration of MMF in Chinese adult renal transplant recipients and to identify factors that explain MPA pharmacokinetic variability. Pharmacokinetic data for MPA and covariate information were retrospectively collected from 118 patients (79 patients were assigned to the group for building the population pharmacokinetic model, while 39 patients were assigned to the validation group). Population pharmacokinetic data analysis was performed using the NONMEM software. The pharmacokinetics of MPA was best described by a two-compartment model with a first-order absorption rate with no lag time. Body weight and serum creatinine level were positively correlated with apparent clearance (CL/F). The polymorphism in uridine diphosphate glucuronosyltransferase gene, UGT2B7, significantly explained the interindividual variability in the initial volume of distribution (V/F). The estimated population parameters (and interindividual variability) were CL/F 18.3 L/h (34.2%) and V/F 27.9 L (21.3%). The interoccasion variability was 13.7%. These population pharmacokinetic data have significant clinical value for the individualization of MMF therapy in Chinese adult renal transplant patients.

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Section: Discussionsupporting

confidence: 53%

Population pharmacokinetics and Bayesian estimation of mycophenolic acid concentrations in Chinese adult renal transplant recipients

Zhou

Wang

et al. 2017

Acta Pharmacol Sin

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“…Clinical studies have shown that UGT1A8 gene polymorphisms not only affect the absorption and metabolism of MMF but also have a certain potential relation with the adverse effects of MMF. 19 However, for the same SNP locus, clinical conclusions have not been completely consistent. [20][21][22][23] This is mainly due to too many confounding factors that are difficult to rule out.…”

Section: Discussionmentioning

confidence: 99%

Untitled

Iemsupakkul

Kongchareonsombat²,

Kijvikai³

2018

Exp Clin Transplant

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Objectives: Mycophenolate mofetil is a first-line drug after organ transplant, but there are differences in metabolism of mycophenolate mofetil among individuals. The UDP glucuronosyltransferase enzyme is the key metabolic enzyme for mycophenolate mofetil, and UGT1A8 gene polymorphisms may affect the elimination of mycophenolate mofetil in patients. Here, we conducted an in vitro study to explore the relation between UGT1A8 gene polymorphisms and mycophenolate mofetil metabolism. Materials and Methods: Five mutant loci overexpression vectors (UGT1A8 128C>T, 157C>A, 431C>T, 518C>G, and 830G>A) were constructed by genetic recombination and site-directed mutagenesis. We used Lipo2000 (Invitrogen, Carlsbad, CA, USA) to transfect the vectors into HEK293 cells. Mycophenolic acid, the active ingredient of mycophenolate mofetil, was added to different groups of cells. We then used the liquid chromatography tandem-mass spectrometry technique to detect production of the metabolite 7-O-mycophenolic acid glucuronide and to evaluate activity of the UDP glucuronosyltransferase enzyme in cells with different overexpression vectors. Results: Mutations of UGT1A8 157C>A and 518C>G vectors can lead to increased activity of UDP glucuronosyltransferase enzymes and increased production of the 7-O-mycophenolic acid glucuronide metabolite, which showed 116% (P < .001) and 107% (P = .0191) production changes of 157C>A and 518C>G mutations, respectively, relative to wild-type UGT1A8. However, mutations of UGT1A8 431C>T and 830G>A loci resulted in decreased activity of UDP glucuronosyltransferase enzymes and decreased production of the metabolite, respectively showing 62.9% (P < .001) and 9.05% (P < .001) activity relative to wild-type UGT1A8. UGT1A8 128C>T had little effect on enzyme activity, with 96.8% activity relative to wild-type UGT1A8 (P = .0569). Conclusions: Our results showed that UGT1A8 gene polymorphisms can affect the activity of UDP glucuronosyltransferase enzyme, which may influence the elimination of mycophenolate mofetil in different patients.

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“…On the other hand, Xie et al. shown that the frequency of TT genotype was higher than Caucasian population [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, Xie et al. reported that there were also no significant differences in either daytime and night time pharmacokinetics of MPA among UGT1A9 CC, CT, and TT genotype groups [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

Influence of uridine diphosphate-glucuronosyltransferases (1A9) polymorphisms on mycophenolic acid pharmacokinetics in patients with renal transplant

et al. 2018

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Background: There are differences in pharmacokinetic of mycophenolic acid among individuals. The UGT1A9 enzyme is of special interest since it is the main enzyme involved in the glucuronidation of MPA. Single nucleotide polymorphisms in the UGT1A9 gene may be responsible for individual differences in the pharmacokinetics of MPA. The aim of this study was to explain MPA pharmacokinetics in UGT1A9 1399 C > T polymorphisms in Turkish renal transplant patients.Patients and methods: One hundred and twenty-five living-donor transplant recipients and 100 healthy control subjects underwent UGT1A9 1399 C > T genotyping using polymerase chain reaction–restriction fragment length polymorphism. Concentrations of MPA were determined with Cloned Enzyme Donor Immunoassay (CEDIA). Besides that, all the patients were monitored for acute rejection and graft function during the study period.Results: The UGT1A9 1399 C > T CC, CT, and TT genotype frequencies among patients were, respectively, 68.0%, 23.2%, and 8.8%. The CC, CT, and TT genotype frequencies among controls were, respectively, 63.0%, 23.0%, and 14.0%. There was no significant difference between patients and controls (p = .480, p = .999, p = .286, respectively). At first month, respectively, through blood concentrations of MPA were significantly higher in UGT1A9 1399 C > T TT carriers than in CT and CC carriers (p = .046). The doses for these patients were lower at first month (p = .021). Acute rejection episodes were not associated with the CC vs CT or TT genotypes (p = .064).Conclusions: Our results demonstrated a correlation between the UGT1A9 1399 C > T polymorphism and MPA pharmacokinetics among renal transplant patients. Determination of UGT1A9 polymorphism may help to achieve target of MPA blood concentrations.

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Associations of UDP-glucuronosyltransferases polymorphisms with mycophenolate mofetil pharmacokinetics in Chinese renal transplant patients

Abstract: The UGT2B7 11+985A>G genotype is associated with the pharmacokinetics of MPA in Chinese renal transplant patients, which demonstrates the usefulness of this SNP for individualizing MMF dosing.

Cited by 32 publications

References 34 publications

Population pharmacokinetics and Bayesian estimation of mycophenolic acid concentrations in Chinese adult renal transplant recipients

Population pharmacokinetics and Bayesian estimation of mycophenolic acid concentrations in Chinese adult renal transplant recipients

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Influence of uridine diphosphate-glucuronosyltransferases (1A9) polymorphisms on mycophenolic acid pharmacokinetics in patients with renal transplant

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