Pharmacokinetic and pharmacodynamic effects of coadministration of methylprednisolone and tacrolimus in rabbits

Tacrolimus, (FK 506) is used for treatment of various organ transplantations in combination with corticosteroids. Rabbits are a good animal model for pharmacokinetic studies of these drugs. The i.v. administration of methylprednisolone (MP; 1.25 mg/kg) (sodium succinate) at 0.5 hr after tacrolimus (0.15 mg/kg) did not influence the disposition of these drugs in rabbits. Clearances of MP were 0.45 liters/hr/kg after given alone and 0.48 liter/hr/kg after tacrolimus. The plasma and whole blood clearances of tacrolimus were 2.18 and 0.21 and 2.35 and 0.19 liters/hr/kg after separate and joint administration with the steroid. The concentrations of corticosterone were variable in all groups and was not useful as a pharmacodynamic parameter. Whole blood histamine concentrations as a marker for basophils did not change after drug administration, but increased over several weeks of experiments. Helper-T cells in rabbits as in humans show a circadian rhythm with an acrophase at 1:00 A.M.. MP and tacrolimus decreased the number of circulating helper-T cells with IC₅₀ values of 23 ng/ml for MP and 6.7 ng/ml for tacrolimus. After coadministration of these drugs, an interaction occurs, but the nature (additive or antagonistic) of this interaction was not clear. The IC₅₀ of tacrolimus for in vitro inhibition of lymphocyte proliferation was 0.39 ng/ml (0.47 nM) and 1.02 ng/ml (2.73 nM) for MP. The maximum percentage of inhibition was 94.6% for tacrolimus and 64.9% for MP. The interaction between low concentrations of tacrolimus (0.1- 0.3 ng/ml) and MP was additive, but mild antagonism was observed at higher concentration of tacrolimus (1 ng/ml). Thus, the nature of the joint immunosuppression effects of tacrolimus and MP in rabbits is probably additive at therapeutic concentrations.