title: Is cyclosporine A transport inhibited by pravastatin via multidrug resistant protein 2?
abstract: OBJECTIVE
  Cyclosporine A (CyA) is an immunosuppressant drug used to treat various autoimmune diseases and transplantations. It has been reported that, in humans, CyA is metabolized by cytochrome P450 (CYP) 3A or excreted by P-glycoprotein/multidrug resistant protein (MRP) 2. Pravastatin, a statin, is used to treat hyperlipidemia and has also been reported to be excreted primarily by MRP2. We observed an increased blood CyA level in a patient following pravastatin administration, suggesting the possibility that CyA interacted with the pravastatin via MRP2. The aim of the study reported here was to investigate the effects of pravastation on CyA transport via MRP2 using a human colon adenocarcinoma (Caco-2) monolayer model system.
  
  
  METHODS
  Calcein, a substrate of MRP families, was first added to the tissue culture medium of the Caco-2 cells, and CyA (5, 50 microM) and pravastatin (0.1, 1.0 mM) were then added to the apical and basolateral sides. After a 30-min incubation, calcein was effluxed from the Caco-2 cells and the level in the culture medium was assayed. CyA was then added to the tissue culture medium of the Caco-2 cells, and pravastatin (0.1, 0.5, 1.0 mM) was added to the apical and basolateral sides. After a 30-min incubation, CyA was effluxed from the Caco-2 cells, and the level in the culture medium was assayed.
  
  
  RESULTS
  The calcein efflux to the apical side was decreased significantly by the addition of pravastatin (1.0 mM) and CyA (5, 50 microM), respectively. The CyA efflux to the apical side was decreased significantly by the addition of pravastatin (1.0 mM).
  
  
  CONCLUSIONS
  Based on these results, we suggest that CyA transport may be competitively inhibited by pravastatin via MRP2.
authors.affiliation: Laboratory of Clinical Pharmacy & Clinical Pharmacokinetics, Osaka University of Pharmaceutical Sciences, Takastuki, Osaka, Japan.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Kato
authors.forename: Mami
authors.initials: M
authors.lastname: Nishide
authors.forename: Chihiro
authors.initials: C
authors.lastname: Kozu
authors.forename: Asuka
authors.initials: A
authors.lastname: Iwamoto
authors.forename: Kazuya
authors.initials: K
authors.lastname: Urashima
authors.forename: Kaoru
authors.initials: K
authors.lastname: Suzuki
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Ijiri
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Hayashi
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Tanaka
mesh_terms: D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects; D016572:Cyclosporine / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D004347:Drug Interactions; D005260:Female; D005452:Fluoresceins / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D006937:Hypercholesterolemia / Q000188:drug therapy; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D017285:Polymyositis / Q000188:drug therapy; D017035:Pravastatin / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D016572:Cyclosporine; D005452:Fluoresceins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007166:Immunosuppressive Agents; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D017035:Pravastatin; C000715087:ABCC2 protein, human; C085925:calcein AM