Research progress of mycophenolate mofetil associated gastroenteritis

doi:10.3877/cma.j.issn.1674-3903.2021.01.013

Abstract

Abstract:

Mycophenolate mofetil (MMF) is an immunosuppressive agent widely used in solid organ transplantation. After oral administration, it is rapidly hydrolyzed into the active drug moiety mycophenolic acid (MPA) in the stomach, which selectively inhibits T/B cell proliferation by inhibiting the activity of inosine-5′-monophosphate dehydrogenase through non-competitive inhibition. MPA inhibits organ rejection and maintains the function of transplanted organs. MMF is generally tolerated by patients, main adverse reactions include gastrointestinal adverse reactions, bone marrow suppression and opportunistic infections. MMF associated gastroenteritis is characterized by diarrhea, weight loss, abdominal discomfort, nausea, vomiting, anorexia, etc. In this paper, we reviewed the pharmacology and pharmacokinetics of MMF, the possible mechanism of MMF associated gastroenteritis, the pathological changes of gastrointestinal tract and its treatment strategies.

Key words: Mycophenolate mofetil, Gastroenteritis, Organ transplantation

Qishun Yang, Lin Zhang, Ya Tuo, Tieqiang Xie, Chibing Hang. Research progress of mycophenolate mofetil associated gastroenteritis[J]. Chinese Journal of Transplantation(Electronic Edition), 2021, 15(01): 55-59.

/ / Recommend

Add to citation manager EndNote|Ris|BibTeX

URL: https://zhyzzz.cma-cmc.com.cn/EN/10.3877/cma.j.issn.1674-3903.2021.01.013

https://zhyzzz.cma-cmc.com.cn/EN/Y2021/V15/I01/55

References 53

1	Farooqi R, Kamal A, Thind K, et al. Mycophenolate-induced colitis: 1546[J]. Official Journal of the American College of Gastroenterology, 2018, 113：S889-S890.
2	Milone MC. Chapter 1 - Overview of the pharmacology and toxicology of immunosuppressant agents that require therapeutic drug monitoring[J]. Personalized Immunosuppression in Transplantation, 2016：1-27.
3	Dhakal P, Gami R, Giri S, et al. Mycophenolate mofetil (MMF)-induced colitis[J]. Blood, 2016, 128：4795.
4	Weigel G, Bertalanffy P, Dubsky P, et al. Mycophenolic acid influences T helper 2 (Th2) cytokine induced expression of intercellular cell adhesion molecule-1 (ICAM-1) on human endothelial cells[J]. Clin Chem Lab Med, 1999, 37(3)：253-257.
5	Dostalek M, Gohh RY, Akhlaghi F, et al. Inosine monophosphate dehydrogenase expression and activity are significantly lower in kidney transplant recipients with diabetes mellitus[J]. Ther Drug Monit, 2013, 35(3)：374-383.
6	Kiang TKL, Ensom MHH. Population pharmacokinetics of mycophenolic acid: An update[J]. Clin Pharmacokinet, 2018, 57(5)：547-558.
7	Božina N, Lalic Z, Nad-Skegro S, et al. Steady-state patients: exploratory analysis of the effects of cyclosporine, recipients′ and donors′ ABCC2 gene variants, and their interactions[J]. Eur J Clin Pharmacol, 2017, 73(9)：1129-1140.
8	Staatz CE, Duffull SB, Kiberd B, et al. Population pharmacokinetics of mycophenolic acid during the first week after renal transplantation[J]. Eur J Clin Pharmacol, 2005, 61(7)：507-516.
9	Krenzien F, ElKhal A, Quante M, et al. A rationale for age-adapted immunosuppression in organ transplantation[J]. Transplantation, 2015, 99(11)：2258-2268.
10	Staatz CE, Tett SE. Maximum a posteriori bayesian estimation of mycophenolic acid area under the concentration-time curve: Is this clinically useful for dosage prediction yet？[J]. Clin Pharmacokinet, 2011, 50(12)：759-772.
11	Amelia R, Cossart W, Neil Cottrell, et al. Characterizing the pharmacokinetics and pharmacodynamics of immunosuppressant medicines and patient outcomes in elderly renal transplant patients[J]. Transl Androl Urol, 2019, 8(Suppl 2)：S198-S213.
12	Veličković-Radovanović R, Mikov M, Paunović G, et al. Gender diferences in harmacokinetics of tacrolimus and their clinical signifcance in kidney transplant recipients[J]. Gend Med, 2011, 8(1)：23-31.
13	Ana Spasić, Aleksandra Catić-Đorđević, Radmila Veličković-Radovanović. Adverse efects of mycophenolic acid in renal transplant recipients: gender diferences[J]. Int J Clin Pharm, 2019, 41(3)：776-784.
14	Kaplan B, Meier-Kriesche HU, Minnick P, et al. Randomized calcineurin inhibitor cross over study to measure the pharmacokinetics of co-administered enteric-coated mycophenolate sodium[J]. Clin Transplant, 2005, 19(4)：551-558.
15	Schaier M, Scholl C, Scharpf D, et al. Proton pump inhibitors interfere with the immunosuppressive potency of mycophenolate mofetil[J]. Rheumatology (Oxford), 2010, 49(11)：2061-2067.
16	Pescovitz MD, Conti D, Dunn J, et al. Intravenous mycophenolate mofetil: safety, tolerability, and pharmacokinetics[J]. 2000, 14(3)：179-188.
17	Bunnapradist S, Sampaio MS, Wilkinson AH, et al. Changes in the small bowel of symptomatic kidney transplant recipients converted from mycophenolate mofetil to enteric-coated mycophenolate sodium[J]. Am J Nephrol, 2014, 40(2)：184-190.
18	Hale MD, Nicholls AJ, Bullingham RE, et al. The pharmaco kinetic-pharmacodynamic relationship for mycophenolate mofetil in renal transplantation[J]. Clin Pharmacol Ther, 64(6)：6726-6783.
19	Kolassa N, Stengg R, Turnheim K. Adenosine uptake by the isolated epithelium of guinea pig jejunum[J]. Can J Physiol Pharmacol, 1977, 55(5)：1033-1038.
20	Arns W. Noninfectious gastrointestinal (GI) complications of mycophenolic acid therapy: a consequence of local GI toxicity？[J]. Transplant Proc, 2007, 39(1)：88-93.
21	George Liapis, John Boletis, Chrysanthi Skalioti, et al. Histological spectrum of mycophenolate mofetil-related colitis: association with apoptosis[J]. Histopathology, 63(5)：649-658.
22	Parfitt JR, Jayakumar S, Driman DK. Mycophenolate mofetilrelated gastrointestinal mucosal injuryvariable injury patterns，including graft-versus-host disease-like changes[J]. Am J Surg Pathol, 2008, 32(9)：1367-1372.
23	Bunnapradist S, Ambühl PM. Impact of gastrointestinal-related side effects on mycophenolate mofetil dosing and potential therapeutic strategies[J]. Clin Transplant, 2008, 22(6)：815-821.
24	Shipkova M, Armstrong VW, Oellerich M, et al. Acyl glucuronide drug metabolites: Toxicological and analytical implications[J]. Ther Drug Monit, 2003, 25(1)：1-16.
25	Bailey MJ, Dickinson RG. Acyl glucuronide reactivity in perspective: Biological consequences[J]. Chem Biol Interact, 2003, 145(2)：117-137.
26	Atchison CR, West AB, Balakumaran A, et al. Drug enterocyte adducts: Possible causal factor for diclofenac enteropathy in rats[J]. Gastroenterology, 2000, 119(6)：1537-1547.
27	Qasim M, Rahman H, Ahmed R, et al. Mycophenolic acid mediated disruption of the intestinal epithelial tight junctions[J]. Exp Cell Res, 2014, 322(2)：277-289.
28	Khan N, Asif AR. Transcriptional regulators of claudins in epithelial tight junctions[J]. Mediators Inflamm, 2015：219843.
29	Khan N, Binder L, Pantakani DVK, et al. MPA modulates tight junctions′ permeability via midkine/PI3K pathway in Caco-2 cells: A possible mechanism of leak-flux diarrhea in organ transplanted patients[J]. Front Physiol, 2017, 8：438.
30	杨其顺，杨加彩，王旭，等. 麦考酚酸酯对小鼠肠道γδT淋巴细胞及血浆IL-6、TNF-α表达的影响[J]. 中华器官移植杂志，2018, 39(3)：158-163.
31	Suzuki T, Yoshinaga N, Tanabe S. Interleukin-6 (IL-6) regulates claudin-2 expression and tight junction permeability in intestinal epithelium[J]. J Biol Chem, 2011, 286(36)：31263-31271.
32	Kamar N, Faure P, Dupuis E, et al. Villous atrophy induced by mycophenolate mofetil in renal transplant patients[J]. Transpl Int, 2004, 17(8)：463-467.
33	Allison AC, Eugui EM. Mechanism of action of mycophenolate mofetil in preventing acute and chronic allograft rejection[J]. Transplantation, 2005, 80(2 Suppl)：S181-S190.
34	Maes BD, Dalle I, Geboes K, et al. Erosive enterocolitis in mycophenolate mofetil-treated renal-transplant recipients with persistent afebrile diarrhea[J]. Transplantation, 2003, 75(5)：665-672.
35	de Andrade LG, Rodrigues MA, Romeiro FG, et al. Clinicopathologic features and outcome of mycophenolate-induced colitis in renal transplant recipients[J]. Clin Transplant, 2014, 28(11)：1244-1248.
36	Calmet FH, Yarur AJ, Pukazhendhi G, et al. Endoscopic and histological features of mycophenolate mofetil colitis in patients after solid organ transplantation[J]. Ann Gastroenterol, 2015, 28(3)：366-373.
37	Selbst MK, Ahrens WA, Robert ME, et al. Spectrum of histologic changes in colonic biopsies in patients treated with mycophenolate mofetil[J]. Mod Pathol, 2009, 22(6)：737-743.
38	von Moos S, Cippà PE, Wüthrich RP, et al. Intestinal infection at onset of mycophenolic acid-associated chronic diarrhea in kidney transplant recipients[J]. Transpl Infect Dis, 2016, 18(5)：721-729.
39	Fernandes MA, Braun HJ, Evason K, et al. De novo inflammatory bowel disease after pediatric kidney or liver transplant[J]. Pediatr Transplant, 2017, 21(1)：10.1111/petr.12835.
40	Roos-Weil D, Ambert-Balay K, Lanternier F, et al. Impact of norovirus/sapovirus-related diarrhea in renal transplant recipients hospitalized for diarrhea[J]. Transplantation, 2011, 92(1)：61-69.
41	Savvidaki E, Papachristou E, Kazakopoulos P, et al. Gastrointestinal disorders after renal transplantation[J]. Transplant Proc, 2014, 46(9)：3183-3186.
42	Di Vico MC, Messina M, Fop F, et al. Recurrent IgA nephropathy after renal transplantation and steroid withdrawal[J]. Clin Transplant, 2018, 32(4)：e13207.
43	Jones-Hughes T, Snowsill T, Haasova M, et al. Immunosuppressive therapy for kidney transplantation in adults: a systematic review and economic model[J]. Health Technol Assess, 2016, 20(62)：1-594.
44	Tierce JC, Porterfield-Baxa J, Petrilla AA, et al. Impact of mycophenolate mofetil (MMF)-related gastrointestinal complications and MMF dose alterations on transplant outcomes and health carecosts in renal recipients[J]. Clin Transplant, 2005, 19(6)：779-784.
45	Bunnapradist S, Ambuhl PM. Impact of gastrointestinal-related side effects on mycophenolate mofetil dosing and potential therapeutic strategies[J]. Clin Transplant, 2008, 22(6)：815-821.
46	Ortega F, Sanchez-Fructuoso A, Cruzado JM, et al. Gastrointestinal quality of life improvement of renal transplant recipients converted from mycophenolate mofetil to enteric-coated mycophenolate sodium drugs or agents: mycophenolate mofetil and enteric-coated mycophenolate sodium[J]. Transplantation, 2011, 92(4)：426-432.
47	Hiramoto LL, Tedesco-Silva H, Medina-Pestana JO, et al. Tolerability of mycophenolate sodium in renal transplant recipients[J]. Int J Clin Pharm, 2018, 40(6)：1548-1558.
48	Budde K, Curtis J, Knoll G, et al. Enteric-coated mycophenolate sodium can be safely administered in maintenance renal transplant patients: results of a 1-year study[J]. Am J Transplant, 2004, 4(2)：237-243.
49	Kamar N, Oufroukhi L, Faure P, et al. Questionnaire-based evaluation of gastrointestinal disorders in de novo renal transplant patients receiving either mycophenolate mofetil or enteric-coated mycophenolate sodium[J]. Nephrol Dial Transplant, 2005, 20(10)：2231-2236.
50	Cunningham R, Jones L, Enki DG, et al. Proton pump inhibitor use as a risk factor for Enterobacteriaceal infection: a case-control study[J]. J Hosp Infect, 2018, 100(1)：60-64.
51	Kofler S, Shvets N, Bigdeli AK, et al. Proton pump inhibitors reduce mycophenolate exposure in heart transplant recipients-aprospective case-controlled study[J]. Am J Transplant, 2009, 9(7)：1650-1656.
52	Maes B, Hadaya K, de Moor B, et al. Severe diarrhea in renal transplant patients: results of the DIDACT study[J]. Am J Transplant, 2006, 6(6)：1466-1472.
53	杨金霞，杨金彩. 益生菌对肠道上皮细胞保护机制的研究进展[J]. 世界华人消化杂志，2015, 23(4): 577-583.

[1]	China Liver Transplant Registry, National Center for Healthcare Quality Management in Liver Transplant, National Quality Control Center for Human Donated Organ Procurement, National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Committee on Transplant Organ Quality Control, Branch of Organ Transplant Physicians of Chinese Medical Doctor Association, Organ Procurement and Allocation Working Committee of the China Hospital Association, National Trauma Medical Center Organ Protection Committee. Chinese expert consensus on organ protection of transplantation (2022 edition) [J]. Chinese Archives of General Surgery(Electronic Edition), 2022, 16(04): 241-254.
[2]	Wenshi Jiang, Xiangxiang He. Analysis of the development characteristics and discipline construction of organ donation globally and in China [J]. Chinese Journal of Transplantation(Electronic Edition), 2023, 17(05): 280-286.
[3]	Branch of Organ Transplant of Chinese Medical Association, Branch of Organ Transplant Physicians of Chinese Medical Doctor Association, Shanghai Pharmaceutical Profession Association. Expert Consensus on the Use of Mycophenolic Acid in Chinese Liver and Kidney Transplant Recipients (2023 edition) [J]. Chinese Journal of Transplantation(Electronic Edition), 2023, 17(05): 257-272.
[4]	Chunrong Ju, Jianxing He, Nanshan Zhong. The application and future prospects of mizoribine in the field of organ transplantation [J]. Chinese Journal of Transplantation(Electronic Edition), 2023, 17(04): 227-231.
[5]	Organ Transplantation and Rehabilitation Committee of Chinese Medical Association of Rehabilitation. Expert consensus on diabetes mellitus after solid organ transplantation in adults [J]. Chinese Journal of Transplantation(Electronic Edition), 2023, 17(04): 205-220.
[6]	Jinran Yang, Xinchang Li, Xiaoping He, Jun Fu, Chengmei Long, Zhiming Chen. Summary and analysis of combined liver and kidney procurement technology without destruction of diaphragm [J]. Chinese Journal of Transplantation(Electronic Edition), 2023, 17(03): 146-151.
[7]	Jianrong Liu, Mingming Fan, Yu Guo. Analysis of clinical characteristics of organ donors at referral [J]. Chinese Journal of Transplantation(Electronic Edition), 2023, 17(03): 129-133.
[8]	Qi Chen, Jiayu Guo, Zhongbao Chen, Xiaoxiong Ma, Tianyu Wang, Jilin Zou, Long Zhang, Zhitao Cai, Tao Qiu, Jiangqiao Zhou. Combined heart and kidney transplantation: a report of 3 cases [J]. Chinese Journal of Transplantation(Electronic Edition), 2023, 17(02): 124-127.
[9]	Qi Chen, Jiayu Guo, Zhongbao Chen, Xiaoxiong Ma, Tianyu Wang, Jilin Zou, Long Zhang, Zhitao Cai, Tao Qiu, Jiangqiao Zhou. Should our screening rules for organ donors be changed under the current COVID-19 pandemic? [J]. Chinese Journal of Transplantation(Electronic Edition), 2023, 17(02): 82-88.
[10]	Mingshi Ren, Rong Wang, Mingyan Wang, Liyue Zhang, Nan Cheng, Yuanbin Wu. The research progress in gene modification strategies and perioperative management of cardiac xenotransplantation [J]. Chinese Journal of Transplantation(Electronic Edition), 2022, 16(03): 183-189.
[11]	Jinjiang Zhu, Ling Bai, Hua Wang, Guozhen Chen, Haiping Liu, Chenguang Ding. The application of blockchain technology in organ donation and transplantation after the death of citizens [J]. Chinese Journal of Transplantation(Electronic Edition), 2022, 16(03): 165-167.
[12]	Chinese College of Transplant Doctors, Chinese Medical Doctor Association;, Chinese Society of Organ Transplantation, Chinese Medical Association. Chinese experts consensus on the management of surgical site infection in solid organ transplantation (2022 edition) [J]. Chinese Journal of Transplantation(Electronic Edition), 2022, 16(03): 129-139.
[13]	Ao Chen, Qiaoyan Lian, Jianheng Zhang, Xin Xu, Bing Wei, Yuhang Cai, Chunyan Wang, Huo Tan, Jianxing He, Chunrong Ju. Progress on post transplant lymphoproliferative disorder [J]. Chinese Journal of Transplantation(Electronic Edition), 2021, 15(05): 307-312.
[14]	Jianrong Liu, Tianwei Xiong, Mi Zhou, Xvxia Wei, Yuling An, Xiaomeng Yi, Lijuan Li, Pinglan Lu, Mingming Fan, Ziyu Li, Yang Yang, Huimin Yi. Effect of donor management scheme on organ donation outcome [J]. Chinese Journal of Hepatic Surgery(Electronic Edition), 2021, 10(06): 589-593.
[15]	Haiyan He, Wenzhao Xie. Preliminary research on family cultural model of voluntary organ donation [J]. Chinese Journal of Clinicians(Electronic Edition), 2022, 16(12): 1269-1275.

Please choose a citation manager

Content to export