title: Consequences of Mrp2 deficiency for diclofenac toxicity in the rat  intestine ex vivo.
abstract: 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 isnot 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.
authors.affiliation: Division of Pharmacokinetics, Toxicology and Targeting, Department of Pharmacy, University of Groningen, The Netherlands
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Niu
authors.forename: Inge A M
authors.initials: IA
authors.lastname: de Graaf
authors.forename: Dennis
authors.initials: D
authors.lastname: van de Vegte
authors.forename: Miriam
authors.initials: M
authors.lastname: Langelaar-Makkinje
authors.forename: Shuichi
authors.initials: S
authors.lastname: Sekine
authors.forename: Geny M M
authors.initials: GM
authors.lastname: Groothuis
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000172:deficiency*; D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics / Q000633:toxicity*; D004008:Diclofenac / Q000493:pharmacokinetics / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects; D007408:Intestinal Absorption / Q000187:drug effects; D007422:Intestines / Q000737:chemistry / Q000187:drug effects*; D008099:Liver / Q000737:chemistry / Q000187:drug effects; D008297:Male; D051381:Rats; D046509:Tissue Culture Techniques
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; C489249:Abcg2 protein, rat; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004008:Diclofenac; D000255:Adenosine Triphosphate