EFFECTS OF THE PHARMACOKINETIC INTERACTION BETWEEN ORALLY-ADMINISTERED SIROLIMUS AND CYCLOSPORINE ON THE SYNERGISTIC PROLONGATION OF HEART ALLOGRAFT SURVIVAL IN RATS

Oral administration, but not continuous intravenous infusion, of sirol imus (SRL) in combination with cyclosporine (CsA) produces a pharmacok inetic interaction, namely increases in the whole blood trough concent rations of SRL ([SRL(WB)]) and CsA ([CsA(WB)]). The effects of this ph armacokinetic interaction on the synergism between SRL and CsA was exa mined in Wistar Furth (RT1(u)) recipients of Buffalo (RT1(b)) heart al lografts. A 14-day course of oral SRL produced dose-dependent prolonga tion of heart allografts: in untreated controls, 0.5 mg/kg SRL per day extended the mean survival time (MST) from 6.4+/-0.5 days to 12.3+/-3 .8 days (P<0.05); SRL at 1.0 mg/kg per day prolonged the MST to 18.0+/ -5.5 days (P<0.01); at 2.0 mg/kg SRL per day, MST was extended to 52.5 +/-13.2 days (P<0.01); and 4.0 mg/kg SRL per day prolonged MST to 90.0 +/-41.1 days (P<0.01). Comparison of the in vivo effects after oral ve rsus continuous intravenous SRL administration suggested that the oral bioavailability of SRL is less than 10%. Combinations of oral SRL and CsA synergistically prolonged heart allograft survival, as documented by combination index values of 0.01-0.64 (combination index <1 indica tes synergistic interaction). In rats treated with dual drug combinati ons, CsA increased the bioavailability of SRL by two- to elevenfold, a nd SRL increased the bioavailability of CsA by two- to threefold, ther eby significantly decreasing the oral effective dose (ED) values for e ach drug. The ED(50) for SRL alone is 2.4 mg/kg per day, which produce s an average [SRL(WB)] of 13.2 ng/ml, The ED(50) for CsA alone is 8.0 mg/kg per day, which produces an average [CsA(WB)] of 1642 ng/ml. Howe ver, when the two drugs are combined, the ED(50) effect is achieved wi th only 0.34 mg/kg SRL per day ([SRL(WB)]=1.1 ng/ml) and 2.1 mg/kg CsA per day ([CsA(WB)]=326 ng/ml), Individually, 0.34 mg/kg SRL per day p roduces an ED(9) with an average [SRL(WB)] of 0.6 ng/ml, and 2.1 mg/kg CsA per day produces an ED(22) with an average [CsA(WB)] of 174 ng/ml , Thus, the pharmacokinetic interaction between oral SRL and CsA contr ibutes to the in vivo synergism between the two drugs.