title: The pharmacodynamic effects of sirolimus and sirolimus-calcineurin inhibitor combinations on macrophage scavenger and nuclear hormone receptors.
abstract: BACKGROUND
  Sirolimus (SIR) alone or in combination with cyclosporine (CsA) or tacrolimus (TAC) are used in solid organ transplantation, but uncertainty remains regarding their respective atherogenic potentials.
  
  
  METHODS
  THP-1 cells were cultured as macrophages and then treated with plasma trough and peak concentration doses of SIR, SIR/CsA or SIR/TAC to assess the time- and dose-dependent mRNA or protein expression of selected atherogenic genes. The selected atherogenic genes included: the macrophage scavenger receptors (MSRs) CD36, CD68, scavenger receptor (SR)-A, SR-BII, and LOX-1; the nuclear hormone receptors peroxisome proliferator activated receptor gamma (PPARgamma) and liver-X-receptor alpha (LXRalpha); and the cholesterol efflux transporter (ABCA-1).
  
  
  RESULTS
  SIR-mediated changes in mRNA included the upregulation of ABCA1, downregulation of CD68, SR-A and SR-BII, and concentration- and/or time-dependent effects on CD36, LOX-1, PPARgamma, and LXRalpha that did not translate into significant protein changes. With SIR/CsA, the protein expressions of PPARgamma and ABCA-1 were downregulated at 8 h. In contrast, with SIR/TAC, PPARgamma, and ABCA-1 protein expressions were upregulated at 8 h.
  
  
  CONCLUSIONS
  Combination results differed from findings with SIR alone, supporting the observed clinical phenotype with calcineurin inhibitors. These findings may provide a rationale for the development of novel drug delivery strategies to mitigate adverse pharmacodynamic responses.
authors.affiliation: Department of Pharmacy, Saint Barnabas Medical Center, 94 Old Short Hills Road, Livingston, New Jersey 07039, USA.
authors.forename: A Scott
authors.initials: AS
authors.lastname: Mathis
authors.forename: Song
authors.initials: S
authors.lastname: Jin
authors.forename: Gary S
authors.initials: GS
authors.lastname: Friedman
authors.forename: Felice
authors.initials: F
authors.lastname: Peng
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Carl
authors.forename: Gregory T
authors.initials: GT
authors.lastname: Knipp
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D050197:Atherosclerosis / Q000139:chemically induced / Q000378:metabolism; D018955:CD36 Antigens / Q000378:metabolism; D065095:Calcineurin Inhibitors; D002460:Cell Line; D016572:Cyclosporine / Q000009:adverse effects / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D000071518:Liver X Receptors; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D051116:Receptors, Scavenger / Q000378:metabolism*; D020123:Sirolimus / Q000009:adverse effects / Q000494:pharmacology*; D016559:Tacrolimus / Q000009:adverse effects / Q000494:pharmacology*; D013997:Time Factors
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D018955:CD36 Antigens; D065095:Calcineurin Inhibitors; D004268:DNA-Binding Proteins; D007166:Immunosuppressive Agents; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D051116:Receptors, Scavenger; D016572:Cyclosporine; D020123:Sirolimus; D016559:Tacrolimus