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 (RT1u) 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 0.01-0.64 (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 ([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 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.
authors.affiliation: Department of Surgery, University of Texas Medical School at Houston, 77030, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Stepkowski
authors.forename: K L
authors.initials: KL
authors.lastname: Napoli
authors.forename: M E
authors.initials: ME
authors.lastname: Wang
authors.forename: X
authors.initials: X
authors.lastname: Qu
authors.forename: T C
authors.initials: TC
authors.lastname: Chou
authors.forename: B D
authors.initials: BD
authors.lastname: Kahan
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D016572:Cyclosporine / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004357:Drug Synergism; D006085:Graft Survival / Q000187:drug effects*; D016027:Heart Transplantation / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male; D011090:Polyenes / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051381:Rats; D011920:Rats, Inbred WF; D020123:Sirolimus
chemical_list: D007166:Immunosuppressive Agents; D011090:Polyenes; D016572:Cyclosporine; D020123:Sirolimus