title: Gender-related assessment of cyclosporine/prednisolone/sirolimus interactions in three human lymphocyte proliferation assays.
abstract: BACKGROUND
  Cyclosporine (CsA), prednisolone (Pred), and sirolimus (Sir) are immunosuppressive compounds inhibiting lymphocyte proliferation at the cytokine gene transcription (CsA and Pred) or signal transduction (Sir) levels.
  
  
  METHODS
  Double- and triple-drug interactions were simultaneously studied using lectin-induced proliferation of isolated cell lymphocytes (ICLP) and whole blood lymphocytes from men and women as well as two-way mixed lymphocyte reaction assays. Drug interactions were described with isobolograms and quantitated with the universal response surface approach by estimating the interaction parameter alpha.
  
  
  RESULTS
  All compounds inhibited more than 89% of control proliferative responses. In each assay, CsA was less potent than Pred (3- to 14-fold) and Sir (5- to 11-fold). Sir was of similar or higher potency than Pred and 1.5-fold more potent in men than women. Pred was 1.4 times more potent in women but this was found only in the ICLP assay. All combinations were synergistic (alpha>0), with greater synergism found for combinations involving Sir, especially in the ICLP (alpha>13) and two-way mixed lymphocyte reaction (alpha>40) assays. Moreover, the Sir/Pred interaction in the ICLP assay was two to five times more synergistic in women, because their mean alpha was 56 compared with 13 in men. Double-combination alpha values were able to reasonably describe CsA/Pred/Sir triple-interaction effects.
  
  
  CONCLUSIONS
  These studies indicate that CsA, Pred, and Sir act and synergistically interact in vitro, with gender and assay as additional factors, and that whole blood lymphocyte proliferation cultures are useful in assessing the nature and intensity of drug interactions.
authors.affiliation: Department of Pharmaceutics, State University of New York at Buffalo, 14260, USA.
authors.forename: G M
authors.initials: GM
authors.lastname: Ferron
authors.forename: N A
authors.initials: NA
authors.lastname: Pyszczynski
authors.forename: W J
authors.initials: WJ
authors.lastname: Jusko
mesh_terms: D000328:Adult; D002455:Cell Division / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007959:Lymphocyte Culture Test, Mixed; D008214:Lymphocytes / Q000166:cytology* / Q000187:drug effects; D008297:Male; D011090:Polyenes / Q000494:pharmacology*; D011239:Prednisolone / Q000494:pharmacology*; D012727:Sex Characteristics; D020123:Sirolimus
chemical_list: D007166:Immunosuppressive Agents; D011090:Polyenes; D016572:Cyclosporine; D011239:Prednisolone; D020123:Sirolimus