Rapamycin: Distribution, Pharmacokinetics, and Therapeutic Range Investigations

Summary Rapamycin (RAPA) is a potent immunosuppressive drug that is presently undergoing clinical trials. The most of the drug is sequestered in erythrocytes resulting in whole blood concentrations being considerably higher than plasma concentrations. The drug is metabolized by the same P450 3A enzyme that is involved in the metabolism of cyclosporine and tacrolimus. Structural elucidation of RAPA metabolites is required. The drug has a relatively long half-life in both humans and animals with 24-h trough concentrations being within the analytic range of high-performance liquid chromatography (HPLC) when immunosuppressive doses are administered. For RAPA, a proportionality is exhibited between trough concentrations and dose. In animal transplant models, trough concentrations of the drug appear to be related to immunosuppressive efficacy and drug-related side effects. The studies described here should provide the basis for establishment of therapeutic monitoring protocols for the drug.