Pharmacokinetic profile of cyclosporine A and G and their effects on cellular immunity and glucose tolerance in male and female Wistar rats.
This study examined the effects of the widely used immunosuppressor cyclosporine A and of one of its derivatives, cyclosporine G, on glucose tolerance, cellular immunity, and renal and hepatic function, in relation to their pharmacokinetic profile in Wistar rats. After 3 weeks of daily cyclosporine A doses of 10 mg/kg body weight plasma cyclosporine levels were higher in male than in female rats. This was associated in male rats with marked decrease in lymphocyte subsets, affecting particularly the OX19+ T cells, with glucose intolerance, and an increase in plasma creatinine. The female rats had none of these effects. After 3 weeks of daily cyclosporine G doses of 10 mg/kg body weight, plasma cyclosporine levels were higher in male than female animals, and higher than with cyclosporine A in both sexes. Similar cellular immune effects and glucose intolerance were seen in male rats, but of a lesser magnitude than with cyclosporine A. No increase in creatinine was seen, but rats of both sexes treated with cyclosporine G had elevated plasma bilirubin. We conclude that (1) both cyclosporine A and G can cause glucose intolerance, (2) the cyclosporine plasma levels are higher in male than in female rats and with cyclosporine G than with cyclosporine A, for the same oral dose, (3) the absence of glucose intolerance, nephrotoxicity, and cellular immune changes in female rats treated with cyclosporine A is related to their lower cyclosporine levels, and (4) cyclosporine G is less nephrotoxic than cyclosporine A, but more hepatotoxic.
Faraci
M
M
McGill Nutrition and Food Science Centre, McGill University, Montreal, Quebec, Canada.
Vigeant
C
C
Yale
J F
JF
D000818:Animals; D001663:Bilirubin / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism*; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine; D003524:Cyclosporins / Q000493:pharmacokinetics* / Q000633:toxicity; D005260:Female; D005951:Glucose Tolerance Test; D007111:Immunity, Cellular / Q000187:drug effects*; D007668:Kidney / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains
D001786:Blood Glucose; D003524:Cyclosporins; C045571:cyclosporin G; D016572:Cyclosporine; D003404:Creatinine; D001663:Bilirubin