Effects of the pharmacokinetic interaction between orally administered sirolimus and cyclosporine on the synergistic prolongation of heart allograft survival in rats Journal Article


Authors: Stepkowski, S. M.; Napoli, K. L.; Wang, M. E.; Qu, X.; Chou, T. C.; Kahan, B. D.
Article Title: Effects of the pharmacokinetic interaction between orally administered sirolimus and cyclosporine on the synergistic prolongation of heart allograft survival in rats
Abstract: Oral administration, but not continuous intravenous infusion, of sirolimus (SRL) in combination with cyclosporine (CsA) produces a pharmacokinetic interaction, namely increases in the whole blood trough concentrations of SRL ([SRL(WB)]) and CsA ([CsA(WB)]). The effects of this pharmacokinetic interaction on the synergism between SRL and CsA was examined in Wistar Furth (RT1(u)) recipients of Buffalo (RT1b) heart allografts. A 14-day course of oral SRL produced dose-dependent prolongation 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 versus 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 0.010.64 (combination index < 1 indicates synergistic interaction). In rats treated with dual drug combinations, CsA increased the bioavailability of SRL by two- to elevenfold, and SRL increased the bioavailability of CsA by two- to threefold, thereby significantly decreasing the oral effective dose (ED) values for each drug. The ED50 for SRL alone is 2.4 mg/kg per day, which produces an average [SRL(WB)] of 13.2 ng/ml. The ED50 for CsA alone is 8.0 mg/kg per day, which produces an average [CsA(WB)] of 1642 ng/ml. However, when the two drugs are combined, the ED50 effect is achieved with only 0.34 mg/kg SRL per day ([SR- L(WB)]=l.1 ng/ml) and 2.1 mg/kg CsA per day ([CsA(WB)] =326 ng/ml). Individually, 0.34 mg/kg SRL per day produces an ED9 with an average [SRL(WB)] of 0.6 ng/ml, and 2.1 mg/kg CsA per day produces an ED22 with an average [CsA(WB)] of 174 ng/ml. Thus, the pharmacokinetic interaction between oral SRL and CsA contributes to the in vivo synergism between the two drugs.
Keywords: adolescent; allograft; drug potentiation; nonhuman; mouse; animals; animal tissue; drug synergism; rat; rats; drug bioavailability; drug blood level; graft rejection; graft survival; immunosuppressive treatment; cyclosporin a; administration, oral; rapamycin; sirolimus; cyclosporine; immunosuppressive agents; biological availability; oral drug administration; heart transplantation; male; priority journal; article; polyenes; rats, inbred wf; heart graft
Journal Title: Transplantation
Volume: 62
Issue: 7
ISSN: 0041-1337
Publisher: Lippincott Williams & Wilkins  
Date Published: 1996-10-15
Start Page: 986
End Page: 994
Language: English
DOI: 10.1097/00007890-199610150-00018
PUBMED: 8878394
PROVIDER: scopus
DOI/URL:
Notes: Article -- Export Date: 22 November 2017 -- Source: Scopus
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MSK Authors
  1. Ting-Chao Chou
    272 Chou