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 tracrolimus. 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).(ABSTRACT TRUNCATED AT 250 WORDS)