Is cyclosporine A transport inhibited by pravastatin via multidrug resistant protein 2?
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.
Kato
Ryuji
R
Laboratory of Clinical Pharmacy & Clinical Pharmacokinetics, Osaka University of Pharmaceutical Sciences, Takastuki, Osaka, Japan.
Nishide
Mami
M
Kozu
Chihiro
C
Iwamoto
Asuka
A
Urashima
Kazuya
K
Suzuki
Kaoru
K
Ijiri
Yoshio
Y
Hayashi
Tetsuya
T
Tanaka
Kazuhiko
K
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
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