The pharmacodynamic effects of sirolimus and sirolimus-calcineurin inhibitor combinations on macrophage scavenger and nuclear hormone receptors.
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.
Mathis
A Scott
AS
Department of Pharmacy, Saint Barnabas Medical Center, 94 Old Short Hills Road, Livingston, New Jersey 07039, USA.
Jin
Song
S
Friedman
Gary S
GS
Peng
Felice
F
Carl
Stephen M
SM
Knipp
Gregory T
GT
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
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