The narrow therapeutic index of cyclosporine (CsA) immunosuppression limits the life-enhancing and life-prolonging benefits of organ transplantation. Our initial studies found that the pharmacokinetic risk factors of low initial and variable long-term oral absorption of CsA correlate with the occurrence of acute and chronic rejection, respectively. A rigorous strategy to control these risk factors by monitoring the area under the concentration-time curve (AUC) only reduced but did not abrogate the incidence of either rejection episodes or nephrotoxic side effects. Therefore, we used the median effect analysis to identify sirolimus (SRL) as a drug that acts synergistically with CsA potentiating its immunosuppressive effects in rat heart and kidney transplant models. However, this combination has some overlapping toxicities, little effect in CsA resistant rat small bowel and murine heart transplants and a prominent pharmacokinetic interaction. The experiments proposed herein first seek to assess the immunosuppressive synergy with CsA of agents that 1) inhibit T cell receptor (TcR)-mediated activation (anti-TcR monoclonal antibodies [MAb]); anti-ICAM-1 or CD4 MAb; ICAM-1 or calcineurin [CaN] antisense oligonucleotides [Oligos]; 2) block cytokine receptor signal transduction (anti-IL-2R); FRAP Oligos, sirolimus [SRL, rapamycin]; or 3 trigger apoptosis (FTY720). Second, we aim to define in vitro surrogates of in vivo drug effects. Third, we intend to apply the median effect analysis to compare the degree of synergy for immunosuppressive versus toxic side effects. Finally, by examining the dose-concentration relationships of individual drugs in combination regimens we seek to identify pharmacokinetic interactions. We intend to detail the pharmacokinetic interactions between CsA and SRL as well as their metabolites by studying cross-inhibition of cytochrome P450 isozyme activity in microsomal preparations and in assays using either crystalline enzymes or products from specific c-DNA transfections of EColi. In aggregate studies seek to describe quantitative the potential benefits and/or risks of CsA-based drug combinations in order to select agents suitable for use in clinical trials.
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