Consequences of Mrp2 deficiency for diclofenac toxicity in the rat intestine ex vivo

- Mrp2 deficient rat intestine ex vivo is intrinsically less sensitive to diclofenac toxicity.
- Lower uptake of diclofenac contributes to the lower diclofenac toxicity in Mrp2− rat intestine.
- Adaptive changes in metabolism and transport in Mrp2− rats are different between liver and intestine.
- Precision cut intestinal slices allow studying drug-induced toxicity in the gut without interference of liver.

The non-steroidal anti-inflammatory drug diclofenac (DCF) has a high prevalence of intestinal side effects in humans and rats. It has been reported that Mrp2 transporter deficient rats (Mrp2−) are more resistant to DCF induced intestinal toxicity. This was explained in vivo by impaired Mrp2-dependent biliary transport of DCF-acylglucuronide (DAG), leading to decreased intestinal exposure to DAG and DCF. However, it is not known to what extent adaptive changes in the Mrp2− intestine itself influence its sensitivity to DCF toxicity without the influence of liver metabolites. To investigate this, DCF toxicity and disposition were studied ex vivo by precision-cut intestinal slices and Ussing chamber using intestines from wild type (WT) and Mrp2− rats. The results show that adaptive changes due to Mrp2 deficiency concerning Mrp2, Mrp3 and BCRP gene expression, GSH content and DAG formation were different between liver and intestine. Furthermore, Mrp2− intestine was intrinsically more resistant to DCF toxicity than its WT counterpart ex vivo. This can at least partly be explained by a reduced DCF uptake by the Mrp2− intestine, but is not related to the other adaptive changes in the intestine. The extrapolation of this data to humans with MRP2 deficiency is uncertain due to species differences in activity and regulation of transporters.