Sites of gastrointestinal lesion induced by mycophenolate mofetil: a comparison with enteric-coated mycophenolate sodium in rats

Yichen Jia,Ming Xu,Jina Wang,Tongyu Zhu,Jiawei Li,Xuanchuan Wang,Guisheng Qi,Ruiming Rong,Rulin Wang,Long Li,Ying Zhang

doi:10.1186/s40360-018-0234-1

Abstract

BackgroundImmunosuppressant drugs for renal transplant mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS) cause gastrointestinal (GI) disorders. The specific site of GI tract targeted by MMF and EC-MPS remains unclear.MethodsIn this study, we investigated the effects of MMF and EC-MPS on stomach, duodenum, jejunum, ileum, colon and rectum using a rat model. Rats were randomized into five groups: control, MMF (100 mg/kg·d), mofetil (30 mg/kg·d), EC-MPS (72 mg/Kg·d), mofetil + EC-MPS. Each group was treated with drugs once a day for 7 days through intra-gastric gavage. Diarrhea grade of each rat were measured every day, as well as the body weight. Blood was collected by tail nick and Seven days later, the rats were sacrificed, GI tissues were collected for Histological research.ResultsThe results showed that diarrhea grade and weight loss were significantly higher in MMF group than other groups. The pathological score of MMF group was significantly higher than EC-MPS group and EC-MPS + mofetil group in jejunum and ileum tissues, but not other segments of GI tract. Absorption of EC-MPS is delayed, compared to that of MMF. MPAG concentration in duodenum, jejunum and ileum tissues of MMF group is higher than EC-MPS group. Mofetil may increase the magnitude of MPA absorption.ConclusionsOur data suggested that MMF might target jejunum and ileum and induce GI injury. EC-MPS causes less injury in GI tract than MMF, probably due to its kinetic property.

Highlights

Immunosuppressant drugs for renal transplant mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS) cause gastrointestinal (GI) disorders
There was no significant difference in the Area under the concentration versus time curve (AUC) values for mycophenolic acid (MPA) or Mycophenolic acid phenolic glucuronide (MPAG) among EC-MPS, MMF and EC-MPS + mofetil groups
The results suggested that clearance of EC-MPS and MMF was the same among these three groups

Summary

Introduction

Immunosuppressant drugs for renal transplant mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS) cause gastrointestinal (GI) disorders. MMF is made from mycophenolic acid (MPA) by ester with N-(2-hydroxyethyl) morpholine (mofetil) It is an immediate-release formulation of MPA and absorbed in the stomach and Mycophenolic acid (MPA) is a nonnucleoside, noncompetitive, potent, selective, and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), which is the rate-limiting enzyme in the de novo synthesis pathway of guanosine triphosphate (GTP) [6]. Both T and B lymphocytes are highly dependent on the generation of GTP, MPA may arrest T- and B-lymphocyte. This enterohepatic circulation recycles MPA, prolonging the half-life of MPA and increasing intestinal exposure of MPA

Methods

Results

Conclusion