Reduced Enterohepatic Recirculation of Mycophenolate and Lower Blood Concentrations Are Associated with the Stool Bacterial Microbiome after Hematopoietic Cell Transplantation

Saqr, Abdelrahman; Carlson, Brooke A.; Staley, Christopher; Rashidi, Armin; Al‐Kofahi, Mahmoud; Kaiser, Thomas; Holtan, Shernan G.; MacMillan, Margaret L.; Young, Jo Anne H.; Jurdi, Najla El; Weisdorf, Daniel J.; Khoruts, Alexander; Jacobson, Pamala A.

doi:10.1016/j.jtct.2022.04.018

Cited by 15 publications

(22 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 2–4 Recently, the microbiota has received attention as a collection of agents that can affect the efficacy of drugs, including immunosuppressants (IS), by altering normal metabolism and/or transport, or by facilitating drug bioaccumulation in cells. 4–8 Mycophenolate mofetil (MMF) is an IS prodrug that is widely used in combination with tacrolimus (TAC) for post-allogeneic hematopoietic cell transplantation (HCT) and kidney transplantation. The active form of MMF, mycophenolic acid (MPA), inhibits the proliferation of T and B lymphocytes thereby reducing the risk of graft- versus -host disease (GVHD), improves stem cell engraftment after HCT, and reduces the risk of allograft rejection after kidney transplant.…”

Section: To the Editormentioning

confidence: 99%

“… 9 Blood MPA concentrations are influenced by enterohepatic recycling (EHR) of MPA due to the de-glucuronidation of MPA glucuronide (MPAG, major inactive metabolite of MMF) by microbial β-glucuronidase post-biliary excretion. 4 , 10 We recently showed that therapeutic concentrations of MPA in the blood of HCT patients were associated with the microbiome composition measured in their fecal samples, although the mechanism for this finding remains unknown. 4 We observed that individuals with therapeutic MPA concentrations were more likely to have β-glucuronidase-producing bacteria in their stool and significantly greater EHR and reformation of MPA.…”

Section: To the Editormentioning

confidence: 99%

“… 4 , 10 We recently showed that therapeutic concentrations of MPA in the blood of HCT patients were associated with the microbiome composition measured in their fecal samples, although the mechanism for this finding remains unknown. 4 We observed that individuals with therapeutic MPA concentrations were more likely to have β-glucuronidase-producing bacteria in their stool and significantly greater EHR and reformation of MPA.…”

Section: To the Editormentioning

confidence: 99%

“…Despite the importance of MMF in facilitating donor engraftment and preventing GVHD, 50% of patients suffer from GVHD and associated non-relapse mortality, 4 , 11 and 5–10% of kidney transplant recipients with have an acute rejection event leading to a higher risk of kidney graft loss. 12 Variability in MPA plasma concentrations among patients affects the potential for adverse clinical outcomes.…”

Section: To the Editormentioning

confidence: 99%

“…In our HCT population, 20 adult (18–75 years) participants undergoing allogeneic transplant for hematologic malignancies were enrolled and are described in our previous study. 4 The HCT study protocol was IRB approved (Study#00005621) and all patients provided written, informed consent. All HCT participants received prophylactic MMF (Cellcept or generic) and TAC (Prograf or generic) at time of stool collection on day +7.…”

Section: To the Editormentioning

confidence: 99%

See 4 more Smart Citations

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

et al. 2022

Self Cite

View full text Add to dashboard Cite

The intestinal microbiota produces β-glucuronidase that plays an essential role in the metabolism of the immunosuppressant mycophenolate mofetil (MMF). This drug is commonly used in organ and hematopoietic cell transplantation (HCT), with variations in dosing across transplant types. We hypothesized that β-glucuronidase activity differs between transplant types, which may account for differences in dosing requirements. We evaluated fecal β-glucuronidase activity in patients receiving MMF post-allogeneic HCT and post-kidney transplant. Kidney transplant patients had significantly greater β-glucuronidase activity (8.48 ± 6.21 nmol/hr/g) than HCT patients (3.50 ± 3.29 nmol/hr/g; P = .001). Microbially mediated β-glucuronidase activity may be a critical determinant in the amount of mycophenolate entering the systemic circulation and an important factor to consider for precision dosing of MMF.

show abstract

Section: To the Editormentioning

confidence: 99%

Section: To the Editormentioning

confidence: 99%

Section: To the Editormentioning

confidence: 99%

Section: To the Editormentioning

confidence: 99%

Section: To the Editormentioning

confidence: 99%

See 3 more Smart Citations

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

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

Oral antibiotics lower mycophenolate mofetil drug exposure, possibly by interfering with the enterohepatic recirculation: A case series

Simoons

Naipal

Jong

et al. 2023

Pharmacology Res & Perspec

View full text Add to dashboard Cite

Mycophenolate mofetil has an important role as immunosuppressive agent in solid organ transplant recipients. Exposure to the active mycophenolic acid (MPA) can be monitored using therapeutic drug monitoring. We present three cases in which MPA exposure severely decreased after oral antibiotic coadministration. By diminishing gut bacteria β‐glucuronidase activity, oral antibiotics can prevent deglucuronidation of the inactive MPA‐7‐O‐glucuronide metabolite to MPA and thereby possibly prevent its enterohepatic recirculation. This pharmacokinetic interaction could result in rejection, which makes it clinically relevant in solid organ transplant recipients, especially when therapeutic drug monitoring frequency is low. Routine screening for this interaction, preferably supported by clinical decision support systems, and pragmatic close monitoring of the MPA exposure in cases is advised.

show abstract

In vitro screening of UGT2B10 in silico prioritized putative ligands from drugs used in the pediatric hematopoietic stem cell transplantation setting

Bennani,

Ben Hassine,

Gencaslan

et al. 2024

Pharmacology Res & Perspec

View full text Add to dashboard Cite

UGT2B10 is a phase II drug metabolizing enzyme with limited information on its role in the metabolism of drugs, especially in the pediatric hematopoietic stem cell transplantation setting. Previously, we investigated UGT2B10's role through in silico analyses and prioritized acetaminophen (APAP), lorazepam (LOR), mycophenolic acid (MPA), and voriconazole N‐oxide (VCZ N‐oxide) for in vitro investigations. In this report, we present in vitro screening of these candidates and of voriconazole (VCZ) to assess their potential to be substrates and/or inhibitors of UGT2B10. Enzyme kinetics experiments included recombinant UGT2B10 and analytical methods based on ultra high‐performance liquid chromatography coupled to mass spectrometry (UHPLC–MS). To determine potential substrates, candidates were incubated at various therapeutically observed concentrations with recombinant UGT2B10 to identify the corresponding glucuronide metabolite. Inhibition capacity was tested using the selective probe cotinine for its glucuronidation to cotinine N‐ß‐d‐glucuronide. IC50 was determined for compounds exhibiting inhibition. Among the tested compounds, LOR (IC50 = 0.01 μM, R2 = 0.9257) and MPA (IC50 = 0.38 mM, R2 = 0.9212) exhibited inhibition potential for UGT2B10. None of the other tested compounds featured inhibition potential and none of the compounds tested exhibited metabolism through UGT2B10. Further exploration on the clinical relevance of this inhibition using modeling strategies, overlapping nature with other UGT isoforms, and screening other molecules for their inhibition potential on UGT2B10 is warranted.

show abstract

Reduced Enterohepatic Recirculation of Mycophenolate and Lower Blood Concentrations Are Associated with the Stool Bacterial Microbiome after Hematopoietic Cell Transplantation

Cited by 15 publications

References 48 publications

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

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

Oral antibiotics lower mycophenolate mofetil drug exposure, possibly by interfering with the enterohepatic recirculation: A case series

In vitro screening of UGT2B10 in silico prioritized putative ligands from drugs used in the pediatric hematopoietic stem cell transplantation setting

Contact Info

Product

Resources

About