Inflammatory bowel disease
Michael JG Farthing, Anne B Ballinger in Drug Therapy for Gastrointestinal and Liver Diseases, 2019
Mycophenolate, through its active metabolite mycophenolic acid, inhibits inosine monophosphate dehydrogenase, an enzyme involved in the synthesis of nucleotides containing the purine base guanine. T and B lymphocytes depend primarily on this nucleotide synthesis for their proliferation in response to antigens. It has been used successfully in organ transplantation to reduce graft rejection and is superior to azathioprine in the prevention of acute rejection. A single, controlled clinical trial has suggested that oral mycophenolate (15 mg/kg mycophenolate mofetil for 6 months) is superior to azathioprine in inducing a remission in patients with chronically active CD and a Crohn’s Disease Activity Index of greater than 300.78 The major side-effects are gastrointestinal upset, leucopenia and sepsis; in renal transplant patients, leucopenia and opportunistic infections occur with similar frequency among mycophenolate and azathioprine-treated patients. Further trials are needed, however, to determine the efficacy as maintenance treatment and long-term toxicity compared with azathioprine. Treatment with mycophenolate should be considered in patients with chronically active CD who are allergic or who have not responded to azathioprine/6-MP.79
Intestinal Transplantation
John K. DiBaise, Carol Rees Parrish, Jon S. Thompson in Short Bowel Syndrome Practical Approach to Management, 2017
Intermediate and long-term immunosuppressive goals include steroid weaning and a reduction in trough serum levels of tacrolimus to avoid cumulative morbidity. In addition to the universal risk for infection with immunosuppression, the well-known adverse effects of prolonged steroid use such as osteoporosis, adrenal insufficiency, peptic ulcer disease, psychosis, cataracts, growth failure in children, and glucose intolerance are augmented by the toxicities associated with other immunosuppressants used in ITx. For tacrolimus, neurotoxicity, nephrotoxicity, glucose intolerance, and hypertension predominate. With mycophenolic acid, bone marrow depression, mucosal ulcerations, and GI disturbances are problematic. The use of mTORi can result in bone marrow depression, nephrotic syndrome, stomatitis, pneumonitis, and dyslipidemia. Weaning of immunosuppression to avoid these complications must be tempered by the long-term risk for acute and chronic rejection, both significant problems after ITx.
Letermovir
M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson in Kucers’ The Use of Antibiotics, 2017
In vitro experiments have shown that letermovir inhibits several enzymes in the human cytochrome P-450 system, including CYP2B6 (half-maximal inhibitory concentration [IC50]: 38 μM), CYP2C8 (IC50: 0.22 μM), and CYP3A4/5 (IC50: 35 μM) (McCormick et al., 2011). Accordingly, healthy volunteers receiving letermovir had a about a 2-fold increase in exposure to both tacrolimus and midazolam, whereas the cyclosporine AUC and Cmax were both increased about 3-fold (McCormick et al., 2011). The pharmacokinetics of mycophenolic acid is unaffected by letermovir, although co-administration may lead to a clinically insignificant increase in letermovir AUC (Marshall et al., 2015). Similarly, letermovir doses of 240 or 480 mg/day had no effect on elimination of digoxin, which is a P-glycoprotein substrate, and only minor effects on absorption or initial distribution; digoxin Cmax was reduced 22%, and AUC was reduced by 12% (Scheuenpflug et al., 2013).
Drugs repurposing for SARS-CoV-2: new insight of COVID-19 druggability
Published in Expert Review of Anti-infective Therapy, 2022
Sujit Kumar Debnath, Monalisha Debnath, Rohit Srivastava, Abdelwahab Omri
Human pluripotent stem cells were used to fabricate colonic organoid and lung models to evaluate the infection target. This cell line is more physiologically relevant than cancer cell lines. Using this model, different FDA-approved drugs were sorted that obstruct the entry of SARS-CoV-2 at physiologically relevant concentrations. Out of them, mycophenolic acid, quinacrine, and imatinib were the most promising candidates [103]. Mycophenolic acid is an immunosuppressant drug used to treat autoimmune conditions like Crohn’s disease and lupus. This drug is also used to prevent rejection during organ transplantations. This drug already showed effectiveness against several viruses like MERS-CoV, human coronavirus (HCoV)-OC43, mouse hepatitis virus, HCoV-NL63, dengue virus, etc. Due to the broad antiviral activity, this drug was explored for COVID-19. An in-vitro antiviral study on VeroE6/TMPRSS2 cells showed a robust cytopathogenic effect (CPE) against COVID-19 [107]. Quinacrine (Qx) is an antimalarial drug that has demonstrated antiviral, antiprion, and anticancer activities. The antiviral activity of Qx is associated with rising pH in acidic organelles, diminishing the enzymatic activity of viral cells, and the ability to bind with viral RNA and DNA. Vero E6 cells line was infected with SARS-CoV-2 to check the antiviral activity of Qx [108]. This study confirmed the reduction of SARS-CoV-2 virus replication and cytotoxicity after 48 h of Qx treatment to the cell line.
MRP4 is responsible for the efflux transport of mycophenolic acid β-d glucuronide (MPAG) from hepatocytes to blood
Published in Xenobiotica, 2021
Joseph Berthier, Mehdi Benmameri, François-Ludovic Sauvage, Gabin Fabre, Benjamin Chantemargue, Hélène Arnion, Pierre Marquet, Patrick Trouillas, Nicolas Picard, Franck Saint-Marcoux
Mycophenolic acid (MPA) is a cornerstone of immunosuppressive therapy, in particular for transplant patients. Currently, two mycophenolic acid-based compounds are available: mycophenolate mofetil and mycophenolate sodium. Following administration, both are rapidly hydrolyzed by carboxylesterases into MPA, the active moiety. MPA is a potent, selective and reversible inhibitor of type II inosine monophosphate dehydrogenase (IMPDH), a key enzyme involved in the de novo synthesis of guanine nucleotides (Franklin & Cook, 1969). In the gastrointestinal tract, the liver and the kidney, MPA is mainly metabolized into a phenyl-β-d glucuronide (MPAG) and into an acyl-glucuronide (AcMPAG) by uridine diphosphate glucuronosyltransferases UGT1A9, 2B7, 1A7, 1A8 and 1A10 (Picard et al., 2005). The 6-O-desmethyl-MPA is another metabolite which is produced by cytochrome P450 3 A isoforms (Picard et al., 2004).
Progress in the pharmacotherapy of uveitis: the art of personalized care
Published in Expert Opinion on Pharmacotherapy, 2022
Shivam H. Patel, Aditya Belamkar, Amir R. Hajrasouliha, Denis Jusufbegovic, Thomas A. Ciulla
Mycophenolate mofetil is a prodrug metabolized to mycophenolic acid that inhibits inosine monophosphate dehydrogenase and guanosine nucleotide synthesis [8]. It has also been found to be very effective for the treatment of many types of uveitis; however, it may require corticosteroid therapy in combination [8]. Mycophenolate mofetil is typically orally administered at 1–2 g daily in a BID fashion [1,5]. Importantly, it must be taken on an empty stomach 2 hours prior to administration and 1 hour after [1]. Azathioprine is a prodrug metabolized to 6-mercaptopurine which acts as an analog of the nucleoside purine [8]. Similarly, it has been found to achieve sustained control of intraocular inflammation in a majority of uveitis patients [8]. It is orally administered, starting between 75 and 100 mg daily, and may be increased to 200–250 mg daily depending on the severity of the inflammation (1,5). Both medications are associated with gastrointestinal issues, malignancies, bone marrow suppression, and increased risk of certain infections [1,5]. Azathioprine may also cause pancreatitis in rare cases [1]. The specific antimetabolite chosen is typically dependent on the preference of the patient and/or physician, preexisting risk factors or morbidities, and previous history of antimetabolite usage [31].
Related Knowledge Centers
- Immunosuppression
- Transplant Rejection
- Organ Transplantation
- Autoimmune Disease
- Crohn's Disease
- Lupus
- Kidney Transplantation
- Heart Transplantation
- Liver Transplantation
- Cancer