The synergistic interactions in vitro and in vivo of brequinar sodium with cyclosporine or rapamycin alone and in triple combination.
The rigorous median-effect analysis was used to assess the interactions between cyclosporine and drugs that inhibit nucleotide synthesis pathways. Using in vitro proliferation assays wherein human lymphocytes were triggered by phytohemagglutin, anti-CD3 monoclonal antibody, or mixed lymphocyte reactions, CsA was shown to display additive interactions with 6-mercaptopurine (6-MP), mizorbine (MZB), and mycophenolic acid (MPA), and a synergistic interaction with brequinar (BQR). In the in vitro assays, BQR contributed a further synergistic effect to the double-drug combination CsA/rapamycin (RAPA). Of the four inhibitors of nucleotide synthesis pathways, only BQR noncompetitively inhibited IL-2-stimulated proliferation of the CTLL-2 cell line. Using the in vivo assay of heterotopic Buffalo (BUF, RT-1b) cardiac allografts in Wistar-Furth (WFu, RT-1u) hosts, oral administration of BQR displayed about 100% bioavailability--which, like the bolus intravenous (i.v.) mode, was eight-fold more effective than continuous i.v. infusions. Furthermore median-effect analysis of serial amounts of orally administered BQR demonstrated that it contributes synergistically to the immunosuppressive effects of intravenously delivered CsA/RAPA (0.5/0.01 mg/kg/day). The degree of synergism was proportionate to the extent of the immunosuppression. These findings document the potency of the CsA/RAPA/BQR triple-drug combination and suggest that the synergistic effects may permit dose reductions of each component, thereby mitigating toxicities resulting from the large amounts of individual agents necessary to achieve allo-unresponsiveness.
Kahan
B D
BD
Department of Surgery, University of Texas Medical School at Houston, Texas 77030.
Tejpal
N
N
Gibbons-Stubbers
S
S
Tu
Y
Y
Wang
M
M
Stepkowski
S
S
Chou
T C
TC
D000906:Antibodies / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology*; D017252:CD3 Complex / Q000276:immunology; D002460:Cell Line / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D007959:Lymphocyte Culture Test, Mixed; D010835:Phytohemagglutinins / Q000494:pharmacology; D011090:Polyenes / Q000494:pharmacology*; D020123:Sirolimus; D013602:T-Lymphocytes, Cytotoxic; D011798:Quinaldines
D000906:Antibodies; D001713:Biphenyl Compounds; D017252:CD3 Complex; D016572:Cyclosporine; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D010835:Phytohemagglutinins; D011090:Polyenes; D020123:Sirolimus; C046943:brequinar; D011798:Quinaldines