Comparison of cyclosporin A and G with and without azathioprine regarding immunosuppressive efficacy, toxicity, and pharmacokinetics in Lewis rats.
Cyclosporin A-associated nephrotoxicity has precipitated the need to develop new immunosuppressive protocols or agents that have a higher therapeutic index than cyclosporin A. A new immunosuppressive agent, cyclosporin G or norvaline (Nva-2) cyclosporine, has been shown to be potent. The rat heterotopic transplant model (ACI to Lewis) and Lewis rats that had no operation were used to compare cyclosporin G with cyclosporin A (5 mg/kg/day per gavage) with and without azathioprine (5 to 10 mg/kg/day, intraperitoneally) in terms of immunosuppressive efficacy (graft survival), toxicity (mortality, renal histopathology, and serum creatinine and blood urea nitrogen values), and pharmacokinetics (trough whole blood cyclosporine levels as measured by radioimmunoassay on days 14 and 28 of treatment). In this model no statistically significant difference in immunosuppression was shown between the two cyclosporins both with and without azathioprine. Cyclosporin G, however, was associated with significantly less mortality when combination therapy with azathioprine was used. Both cyclosporins were associated with normal serum creatinine values and little histopathologic evidence of nephrotoxicity, except juxtaglomerular apparatus hyperplasia. Comparable cyclosporine levels were achieved when cyclosporin A or G was used as the sole immunosuppressive agent, but significantly higher cyclosporine levels were shown with cyclosporin A than with cyclosporin G when combination therapy with azathioprine was used. Further studies in humans are needed to evaluate whether cyclosporin G will be a clinically useful immunosuppressive agent either alone or combined with other immunosuppressive modalities.
Hagberg
R C
RC
Stanford University School of Medicine, CA.
Hoyt
E G
EG
Billingham
M E
ME
Sibley
R K
RK
Starnes
V A
VA
Baldwin
J C
JC
D000818:Animals; D001379:Azathioprine / Q000494:pharmacology* / Q000633:toxicity; D016572:Cyclosporine; D003524:Cyclosporins / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D004359:Drug Therapy, Combination; D016027:Heart Transplantation; D006965:Hyperplasia; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D007606:Juxtaglomerular Apparatus / Q000187:drug effects / Q000473:pathology; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew
D003524:Cyclosporins; D007166:Immunosuppressive Agents; C045571:cyclosporin G; D016572:Cyclosporine; D001379:Azathioprine