After clinical transplantation of an organ such as the liver, the immunosuppressive drug cyclosporine A (CsA) is administered chronically, along with an antiinflammatory corticosteroid, to prevent rejection. Numerous anecdotal reports have recently appeared suggesting that a substantial number of drugs adversely interact with CsA, causing an increased incidence of either nephrotoxicity organ rejection. It is our objective to clarify the underlying mechanisms of adverse drug interactions with CsA in animals in order that such interactions can be anticipated clinically and monitored, or avoided. The effect of other drugs on the pharmacokinetics of CsA will be examined in a dog model. The specific drug interactions with CsA which will be examined are listed: 1. Corticosteroids have been suggested to affect CsA blood levels and vice-versa. The acute and chronic effects at both low and high dose of the corticosteroid prednisolone on CsA pharmacokinetics and the acute and chronic effects of CsA on low and high dose prednisolone pharmacokinetics will, therefore, be examined. 2. Ketoconazole has been reported to drastically increase blood levels of CsA causing nephrotoxicity. The acute and chronic effects of ketoconazole on CsA pharmacokinetics will, therefore, be examined. 3. Rifampicin has been reported to drastically decrease blood levels of CsA causing organ rejection. The acute and chronic effects of rifampicin on CsA pharmacokinetics will, therefore, be examined. Hepatic elimination is the major route of elimination of CsA. Pharmacokinetics studies alone will not distinguish between drug interactions occurring at the level of hepatic metabolism or biliary excretion, but will require separate biliary excretion and in vivo and in vitro CsA metabolism studies.
