Is Conversion from Mycophenolate Mofetil to Enteric-Coated Mycophenolate Sodium Justifiable for Gastrointestinal Quality of Life?

Gardiner, Kyle M.; Tett, S. E.; Staatz, C. E.

doi:10.1007/s40268-018-0254-8

Cited by 10 publications

(4 citation statements)

References 42 publications

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“…The use of MMF as an immunosuppressant is frequently limited by GI side effects. Attempts to relieve toxicity by modifying drug delivery, either through use of an enteric-coating or intravenous administration, have not been successful (21)(22)(23). The metabolism of MMF and MPA have been well described, but the mechanism of toxicity has remained elusive.…”

Section: Discussionmentioning

confidence: 99%

Vancomycin Relieves Mycophenolate Mofetil-Induced Gastrointestinal Toxicity by Eliminating Gut Bacterial β-Glucuronidase Activity

Taylor

Flannigan

Rahim

et al. 2019

Preprint

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Mycophenolate mofetil (MMF) is commonly prescribed after transplantation and has proven advantages over other immunosuppressive drugs but gastrointestinal (GI) side effects frequently limit its use. The pathways involved in the metabolism of the prodrug MMF and the bioactive derivative mycophenolic acid (MPA) are well characterized but the mechanism responsible for toxicity is unknown. Here we extend our previous observation that an intact gut microbiome is required for MMF-induced toxicity and demonstrate that gut bacterial metabolism is responsible for the GI inflammation and weight loss associated with MMF exposure. In mice consuming MMF, the introduction of vancomycin alone was sufficient to prevent or reverse MMF-induced weight loss and colonic inflammation. MMF induced the expansion of bacteria expressing b-glucuronidase (GUS) in the cecum and proximal colon. GUS activity, which is responsible for the catabolism of glucuronidated MPA (MPAG) to free MPA, was increased in the presence of MMF and eliminated by vancomycin. Vancomycin eliminated multiple Bacteroides spp. that flourished in the presence of MMF and prevented the breakdown of MPAG without negatively affecting serum MPA levels. Human data suggests that increased stool GUS activity can be associated with MMF-related toxicity. Our work provides a mechanism for the GI toxicity associated with MMF and a future direction for the development of therapeutics.3

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Section: Discussionmentioning

confidence: 99%

Vancomycin Relieves Mycophenolate Mofetil-Induced Gastrointestinal Toxicity by Eliminating Gut Bacterial β-Glucuronidase Activity

Taylor

Flannigan

Rahim

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…Fractionated doses per day taken with the meals improve gastro-intestinal tolerance. A systematic review of the gastro-intestinal side effects between the two formulations did not demonstrate significant differences between gastrointestinal-related QoL for patients using either form as maintenance immunosuppression (106).…”

Section: Mycophenolate [Recommendation #15]mentioning

confidence: 91%

The 2021 European Group on Graves’ orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves’ orbitopathy

Bartalena

Kahaly

Baldeschi

et al. 2021

European Journal of Endocrinology

462

497

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Graves’ orbitopathy (GO) is the main extrathyroidal manifestation of Graves’ disease (GD). Choice of treatment should be based on assessment of clinical activity and severity of GO. Early referral to specialized centers is fundamental for most patients with GO. Risk factors include smoking, thyroid dysfunction, high serum level of thyrotropin receptor antibodies, radioactive iodine (RAI) treatment, and hypercholesterolemia. In mild and active GO, control of risk factors, local treatments and selenium (selenium-deficient areas) are usually sufficient; if RAI treatment is selected to manage GD, low-dose oral prednisone prophylaxis is needed, especially if risk factors coexist. For both active moderate-to-severe and sight threatening GO, antithyroid drugs are preferred when managing Graves’ hyperthyroidism. In moderate-to-severe and active GO, intravenous (iv) glucocorticoids are more effective and better tolerated than oral glucocorticoids. Based on current evidence and efficacy/safety profile, costs and reimbursement, drug availability, long-term effectiveness and patient choice after extensive counselling, a combination of iv methylprednisolone and mycophenolate sodium is recommended as first-line treatment. A cumulative dose of 4.5 grams (g) of iv methylprednisolone in 12 weekly infusions is the optimal regimen. Alternatively, higher cumulative doses not exceeding 8 g can be used as monotherapy in most severe cases and constant/inconstant diplopia. Second-line treatments for moderate-to-severe and active GO include: a) a second course of iv methylprednisolone (7.5 g) subsequent to careful ophthalmic and biochemical evaluation, b) oral prednisone/prednisolone combined with either cyclosporine or azathioprine; c) orbital radiotherapy combined with oral or iv glucocorticoids, d) teprotumumab; e) rituximab and f) tocilizumab. Sight threatening GO is treated with several high single doses of iv methylprednisolone per week and, if unresponsive, with urgent orbital decompression. Rehabilitative surgery (orbital decompression, squint and eyelid surgery) is indicated for inactive residual GO manifestations.

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“…The use of MMF as an immunosuppressant is frequently limited by GI side effects. Attempts to relieve toxicity by modifying drug delivery, either through use of an enteric coating or intravenous administration, have not been successful ( 11 , 12 ). The metabolism of MMF and MPA has been well described, but the mechanism of toxicity has remained elusive.…”

Section: Discussionmentioning

confidence: 99%

Vancomycin relieves mycophenolate mofetil–induced gastrointestinal toxicity by eliminating gut bacterial β-glucuronidase activity

et al. 2019

View full text Add to dashboard Cite

Mycophenolate mofetil (MMF) is commonly prescribed and has proven advantages over other immunosuppressive drugs. However, frequent gastrointestinal side effects through an unknown mechanism limit its use. We have found that consumption of MMF alters the composition of the gut microbiota, selecting for bacteria expressing the enzyme β-glucuronidase (GUS) and leading to an up-regulation of GUS activity in the gut of mice and symptomatic humans. In the mouse, vancomycin eliminated GUS-expressing bacteria and prevented MMF-induced weight loss and colonic inflammation. Our work provides a mechanism for the toxicity associated with MMF and a future direction for the development of therapeutics.

show abstract

Is Conversion from Mycophenolate Mofetil to Enteric-Coated Mycophenolate Sodium Justifiable for Gastrointestinal Quality of Life?

Cited by 10 publications

References 42 publications

Vancomycin Relieves Mycophenolate Mofetil-Induced Gastrointestinal Toxicity by Eliminating Gut Bacterial β-Glucuronidase Activity

Vancomycin Relieves Mycophenolate Mofetil-Induced Gastrointestinal Toxicity by Eliminating Gut Bacterial β-Glucuronidase Activity

The 2021 European Group on Graves’ orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves’ orbitopathy

Vancomycin relieves mycophenolate mofetil–induced gastrointestinal toxicity by eliminating gut bacterial β-glucuronidase activity

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