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

Abstract

Background: Immunosuppressant 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.

Methods: In 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.

Results: The 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.

Conclusions: Our 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.

Keywords: Enteric-coated mycophenolate sodium; GI side effects; Mycophenolate mofetil; Pharmacokinetics.

Fig. 1

The effects of MMF and EC-MPS on the body weight. Treatment of rats with MMF resulted in significant more loss of body weight than control group (199.5 ± 8.3 g vs 279.8 ± 7.5, p < 0.05) and EC-MPS treatment group (199.5 ± 8.3 g vs 257.8 ± 9.6, p < 0.05)

Fig. 2

The effects of MMF and EC-MPS on the diarrhea score. Treatment of rats with MMF resulted in significant increases in the diarrhea score, compared with the control group (1.375 ± 0.34 vs 0 ± 0, p < 0.05) and EC-MPS treatment group (1.375 ± 0.34 vs 0.125 ± 0.04, p < 0.05)

Fig. 3

Comparisons of the histological scores in GI tract. Comparisons of the histological scores in stomach, duodenum, jejunum, ileum, colon, and rectum among rats treated with indicated drugs in (1) EC-MPS group; (2) MMF group; (3) EC-MPS + mofetil (E + M) group; (4) mofetil (M) group. The histopathological score of the jejunum and ileum segments were significantly higher in the MMF group than the EC-MPS group (4.1 ± 0.3 vs 3.2 ± 0.15, p < 0.05) and EC-MPS + mofetil group (4.1 ± 0.3 vs 3.3 ± 0.18, p < 0.05). There was no significant difference in the histopathological score of the other tissues among MMF group, EC-MPS group, and EC-MPS + mofetil group

Fig. 4

Comparisons of the MPAG levels in GI tract. Comparisons of the MPAG levels in stomach, duodenum, jejunum, ileum, colon, and rectum among rats treated with indicated drugs in (1) EC-MPS group; (2) MMF group; (3) EC-MPS + mofetil (E + M) group. MPAG levels in duodenum, jejunum, and ileum tissues were significantly higher in the MMF group than EC-MPS group (152.4 ± 24.34 vs 72.3 ± 24.23, p < 0.05; 312.3 ± 40.34 vs 208.5 ± 47.34, p < 0.05; 71.2 ± 28.22 vs 42.2 ± 16.43, p < 0.05) and EC-MPS+ mofetil group (152.4 ± 24.34 vs 72.1 ± 15.23, p < 0.05; 312.3 ± 40.34 vs 180.7 ± 21.14, p < 0.05; 71.2 ± 28.22 vs 52.4 ± 17.15, p < 0.05). There was no significant difference in the MPAG levels in stomach, colon, and rectum tissues among all these three groups. In all GI tissues, there are no significant difference between EC-MPS group and EC-MPS+ mofetil group