Piekoszewski W, Chow F S, Jusko W J
Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo.
J Pharmacol Exp Ther. 1994 Apr;269(1):103-9.
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)
他克莫司（FK 506）与皮质类固醇联合用于各种器官移植的治疗。兔子是这些药物药代动力学研究的良好动物模型。在给予他克莫司（0.15 mg/kg）0.5小时后静脉注射甲泼尼龙（MP；1.25 mg/kg）（琥珀酸钠），不影响这些药物在兔子体内的处置。单独给予MP时其清除率为0.45升/小时/千克，与他克莫司合用时为0.48升/小时/千克。单独及与类固醇联合给药后，他克莫司的血浆和全血清除率分别为2.18和0.21以及2.35和0.19升/小时/千克。所有组中皮质酮浓度均有变化，不作为药效学参数。作为嗜碱性粒细胞标志物的全血组胺浓度在给药后未改变，但在数周实验中有所增加。兔子体内的辅助性T细胞与人一样呈现昼夜节律，高峰期在凌晨1点。MP和他克莫司可减少循环辅助性T细胞数量，MP的IC50值为23 ng/ml，他克莫司为6.7 ng/ml。这些药物联合给药后会发生相互作用，但这种相互作用的性质（相加或拮抗）尚不清楚。他克莫司体外抑制淋巴细胞增殖的IC50为0.39 ng/ml（0.47 nM），MP为1.02 ng/ml（2.73 nM）。他克莫司的最大抑制百分比为94.6%，MP为64.9%。低浓度他克莫司（0.1 - 0.3 ng/ml）与MP之间的相互作用是相加性的，但在较高浓度他克莫司（1 ng/ml）时观察到轻度拮抗作用。（摘要截断于250字）
