Fecal β-glucuronidase activity differs between hematopoietic cell and kidney transplantation and a possible mechanism for disparate dose requirements

Khan, Mohammad Haneef; Onyeaghala, Guillaume C.; Rashidi, Armin; Holtan, Shernan G.; Khoruts, Alexander; Israni, Ajay K.; Jacobson, Pamala A.; Staley, Christopher

doi:10.1080/19490976.2022.2108279

Cited by 8 publications

(4 citation statements)

References 33 publications

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“…Decreases in the MPA concentration caused by administration of oral antibiotics has been reported in renal or liver transplant recipients ( 10 , 11 ). However, HSCT patients have many differences from those undergoing solid organ transplantation ( 16 , 17 ). We believe we are the first to study the effect of IV antibiotics on MPA C 0 in the HSCT patients when EHR of MPA is interrupted.…”

Section: Discussionmentioning

confidence: 99%

Impact of carbapenem antibiotics on mycophenolate mofetil in hematopoietic stem cell transplant patients with interruption of the enterohepatic recycling: a retrospective study

Tian¹,

Miao²,

Yan³

et al. 2023

Ann Transl Med

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Background Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), is widely used in the prophylaxis for graft-versus-host disease (GVHD) following hematopoietic stem cell transplantation (HSCT). MPA undergoes enterohepatic recycling (EHR). Oral antibiotics can affect MPA concentration by reducing intestinal flora-mediated EHR. However, the effect of intravenous antibiotics on MPA concentration is not clear, especially in patients whose EHR is already interrupted. This study was conducted to determine whether intravenous carbapenem antibiotics (CBP) influence the pre-dose plasma concentration (C 0 ) of MPA in HSCT patients when the EHR of MPA is interrupted by cyclosporine and gut decontamination. Methods The HSCT patients who received immunosuppressive therapy with MMF and cyclosporine, as well as treatment with CBP were screened as potential candidates. Patients who lacked MPA C 0 measurements before or during CBP use, had combination therapy of rifampin with MMF, or switched from IV to oral MMF were excluded. The liver/renal function, demographic information, albumin/cyclosporine concentration, MPA C 0 and medication information were collected. The changes in the MPA C 0 before and during CBP use were evaluated, and the influence of related clinical factors was also estimated. Results CBP resulted in a significant reduction in the MPA C 0 from 0.65±0.33 to 0.43±0.30 µg/mL. Linear regression analysis indicated a weak correlation between the dose-normalized C 0 of MPA and the dosage of CBP during CBP use (r 2 =0.129, P=0.009). Univariate and multivariate analysis confirmed that the MPA C 0 had no relevance to rifaximin administration (P=0.249–0.700), demographics (P=0.118–0.599), fluctuation of plasma albumin (ALB, P=0.943 and 0.609) and cyclosporine concentrations (P=0.647 and 0.112), or liver and renal functions (P=0.078–0.887) no matter whether the CBP were used. However, compared with the non-gut decontamination group, larger interindividual variabilities and smaller decreases in MPA C 0 (6.60% vs. 41.73%) during CBP therapy were seen in the gut decontamination group, although it was a nonsignificant trend. Conclusions CBP decreased the MPA C 0 in Chinese HSCT patients even when MMF is used in combination with cyclosporine and rifaximin. If antibiotics must be used, and CBP in particular, therapeutic drug monitoring should be performed to ensure adequate exposure.

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Section: Discussionmentioning

confidence: 99%

Impact of carbapenem antibiotics on mycophenolate mofetil in hematopoietic stem cell transplant patients with interruption of the enterohepatic recycling: a retrospective study

Tian¹,

Miao²,

Yan³

et al. 2023

Ann Transl Med

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“…In addition to SNP differences, the metabolic capacity of gut microbiota also actively participates in the utilization and metabolism of MMF e.g. through β-glucuronidase (GUS) enzymes expressed by gut commensals [35][36][37]. We profiled the microbiomes of NMOSD patients that were grouped according to their therapeutic responses to MMF therapy.…”

Section: Discussionmentioning

confidence: 99%

Integrative analysis of purine metabolites and gut microbiota in patients with neuromyelitis optica spectrum disorders after mycophenolate mofetil treatment

Li,

Ma,

Xia

et al. 2023

BMC Neurol

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Background Neuromyelitis optica spectrum disorder (NMOSD) is a recurring inflammatory demyelinating disease that is commonly observed in Asian countries like China. Prior investigations have shown that mycophenolate mofetil (MMF) with better biocompatibility compared to azathioprine (AZA), and can prevent relapses of NMOSD, but the efficacy was controversially reported in different NMOSD cases. We aimed to explore the factors that weaken efficacy of MMF in NMOSD. Methods A total of 34 NMOSD patients treated with MMF were prospectively enrolled and grouped according to the therapeutic efficacy as effective group (EG, n = 23) versus less-effective group (LEG, n = 11). The purine metabolites were profiled in serum samples and gut microbiota was analyzed using 16S rRNA sequencing with stool samples from the same patients. Results Purine salvage pathway (PSP) metabolites (inosine, hypoxanthine, xanthine, guanine and uric acid) in the serum of NMOSD patients were elevated in the LEG compared to EG (p < 0.05). Additionally, the richness and microbial diversity of gut microbiota was found to be similar between EG and LEG patients. However, LEG patients had increased presence of Clostridium and Synergistes but decreased abundance of the Coprococcus genus. Conclusions The PSP metabolites and composition of the gut microbiota were changed between patients with or without optimal clinical response after MMF treatment. This may help us to understand the pharmacodynamics of MMF in NMOSD.

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“…In addition, this correlated with long duration of diarrhea. Finally, in a recent study from Khan et al [ 68 ] fecal β-glucuronidase activity was different between KT patients and hema topoietic cell transplant patients. This fact could explain the different dose requirements of MMF between KT patients.…”

Section: Influence On Immunosuppressive Drug Metabolism Induced By Gu...mentioning

confidence: 96%

Update on the reciprocal interference between immunosuppressive therapy and gut microbiota after kidney transplantation

Salvadori,

Rosso

2024

World J Transplant

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Gut microbiota is often modified after kidney transplantation. This principally happens in the first period after transplantation. Antibiotics and, most of all, immunosuppressive drugs are the main responsible. The relationship between immunosuppressive drugs and the gut microbiota is bilateral. From one side immunosuppressive drugs modify the gut microbiota, often generating dysbiosis; from the other side microbiota may interfere with the immunosuppressant pharmacokinetics, producing products more or less active with respect to the original drug. These phenomena have influence over the graft outcomes and clinical consequences as rejections, infections, diarrhea may be caused by the dysbiotic condition. Corticosteroids, calcineurin inhibitors such as tacrolimus and cyclosporine, mycophenolate mofetil and mTOR inhibitors are the immunosuppressive drugs whose effect on the gut microbiota is better known. In contrast is well known how the gut microbiota may interfere with glucocorticoids, which may be transformed into androgens. Tacrolimus may be transformed by microbiota into a product called M1 that is 15-fold less active with respect to tacrolimus. The pro-drug mycophenolate mofetil is normally transformed in mycophenolic acid that according the presence or not of microbes producing the enzyme glucuronidase, may be transformed into the inactive product.

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Fecal β-glucuronidase activity differs between hematopoietic cell and kidney transplantation and a possible mechanism for disparate dose requirements

Cited by 8 publications

References 33 publications

Impact of carbapenem antibiotics on mycophenolate mofetil in hematopoietic stem cell transplant patients with interruption of the enterohepatic recycling: a retrospective study

Impact of carbapenem antibiotics on mycophenolate mofetil in hematopoietic stem cell transplant patients with interruption of the enterohepatic recycling: a retrospective study

Integrative analysis of purine metabolites and gut microbiota in patients with neuromyelitis optica spectrum disorders after mycophenolate mofetil treatment

Update on the reciprocal interference between immunosuppressive therapy and gut microbiota after kidney transplantation

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