The pharmacodynamic effects of sirolimus and sirolimus-calcineurin inhibitor combinations on macrophage scavenger and nuclear hormone receptors.

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Mathis AS, Jin S, Friedman GS, Peng F, Carl SM, Knipp GT

The pharmacodynamic effects of sirolimus and sirolimus-calcineurin inhibitor combinations on macrophage scavenger and nuclear hormone receptors.

J Pharm Sci. 2007 Jan;96(1):209-22.

PubMed ID

17016853 [ View in PubMed

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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.