Effects of cyclosporin at various concentrations on dexamethasone intracellular uptake in multidrug resistant cells.
BACKGROUND
The multidrug resistance phenomenon results from the expression of P-glycoprotein (P-gp), a drug-efflux pump. Corticosteroids are substrates for P-gp, whose function can be inhibited by cyclosporin. This study evaluates the ability of cyclosporin to modulate dexamethasone uptake in multidrug resistant cells.


METHODS
The K 562 cell line, which does not express P-gp and a P-gp expressing clone, K562/ADM, were used. Cells were incubated with H3-dexamethasone in the absence or presence of cyclosporin at various concentrations. Then, cells were washed, lysed, and radioactivity was measured.


RESULTS
The uptake of dexamethasone alone was higher in sensitive than in resistant cells. Addition of cyclosporin induced a dose dependent increase of dexamethasone uptake in resistant cells, whereas the drug did not influence dexamethasone uptake in parental cells.


CONCLUSIONS
Cyclosporin, at therapeutic concentrations induces a moderate, but significant increase in dexamethasone accumulation in multidrug resistant cells. Thus, cyclosporin might increase the intestinal absorption of corticosteroids or their accumulation in mononuclear cells, or both, thereby increasing their therapeutic efficacy.
Maillefert
J F
JF
Department of Rheumatology, Dijon University Hospital, France.
Duchamp
O
O
Solary
E
E
Genne
P
P
Tavernier
C
C
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000893:Anti-Inflammatory Agents / Q000493:pharmacokinetics*; D018501:Antirheumatic Agents / Q000494:pharmacology*; D016572:Cyclosporine / Q000494:pharmacology*; D003907:Dexamethasone / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D020014:K562 Cells / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000893:Anti-Inflammatory Agents; D018501:Antirheumatic Agents; D005938:Glucocorticoids; D003907:Dexamethasone; D016572:Cyclosporine