Chakraborty A, Blum R A, Cutler D L, Jusko W J
Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo, 14260, USA.
Clin Pharmacol Ther. 1999 Mar;65(3):304-18. doi: 10.1016/S0009-9236(99)70110-4.
The pharmacoimmunodynamic interactions of recombinant human interleukin-10 and prednisolone were examined in 12 normal male volunteers.
Single doses of interleukin-10 (8 microg/kg subcutaneous injection), interleukin-10 with prednisone (15 mg by mouth), placebo with prednisone, or placebo were administered. Drug concentrations yielded pharmacokinetic parameters. Response measurements included whole blood lipopolysaccharide-stimulated cytokine (tumor necrosis factor-alpha, interleukin-1beta) production, phytohemagglutinin-stimulated whole blood lymphocyte proliferation, and differential white blood cell counts (including monocytes, lymphocytes, and neutrophils). Extended indirect-response models were used to deal with diverse drug interactions in assessing single and joint effects of interleukin-10 and prednisolone.
No pharmacokinetic alterations in interleukin-10 or prednisolone were found. Dosing with interleukin-10 produced strong inhibition of ex vivo cytokine production for the 24-hour postdosing period, whereas prednisolone, the active form of prednisone, was partly inhibitory for only 3 hours. Prednisolone significantly inhibited (P < .05) ex vivo lymphocyte proliferation for 6 hours, whereas interleukin-10 failed to alter this measure. Their joint effects on these responses were inhibitory consonant with the stronger agent. Marked changes in various leukocyte kinetics occurred. The steroid caused monocytopenia, lymphocytopenia, and neutrophilia, with IC50 or SC50 values of 10 to 20 ng/mL. Interleukin-10 elevated monocytes and neutrophils and lowered lymphocyte counts, with IC50 or SC50 values of 0.7 to 1.3 ng/mL. Dynamic modeling showed loss of prednisolone effects on monocytes and additive steroid/interleukin-10 effects on lymphocytes and neutrophils, with neutrophils exhibiting greater changes in net response.
Interleukin-10 and prednisolone interacted favorably for the measured pharmacoimmunodynamic indices with no kinetic alterations but net responses that were similar to or greater than effects produced by the more strongly acting agent.
在12名正常男性志愿者中研究重组人白细胞介素-10与泼尼松龙的药物免疫动力学相互作用。
分别给予单剂量的白细胞介素-10（8μg/kg皮下注射）、白细胞介素-10与泼尼松（口服15mg）、安慰剂与泼尼松或安慰剂。药物浓度得出药代动力学参数。反应测量包括全血脂多糖刺激的细胞因子（肿瘤坏死因子-α、白细胞介素-1β）产生、植物血凝素刺激的全血淋巴细胞增殖以及白细胞分类计数（包括单核细胞、淋巴细胞和中性粒细胞）。使用扩展间接反应模型来处理评估白细胞介素-10和泼尼松龙的单一及联合效应时的各种药物相互作用。
未发现白细胞介素-10或泼尼松龙的药代动力学改变。给予白细胞介素-10在给药后24小时内对体外细胞因子产生有强烈抑制作用，而泼尼松的活性形式泼尼松龙仅在3小时内有部分抑制作用。泼尼松龙在6小时内显著抑制（P<.05）体外淋巴细胞增殖，而白细胞介素-10未能改变这一指标。它们对这些反应的联合效应与较强作用药物一致，具有抑制性。各种白细胞动力学发生了显著变化。类固醇导致单核细胞减少、淋巴细胞减少和中性粒细胞增多，IC50或SC50值为10至20ng/mL。白细胞介素-10使单核细胞和中性粒细胞增多，淋巴细胞计数降低，IC50或SC50值为0.7至1.3ng/mL。动态建模显示泼尼松龙对单核细胞的作用丧失，类固醇/白细胞介素-10对淋巴细胞和中性粒细胞有相加作用，中性粒细胞的净反应变化更大。
白细胞介素-10和泼尼松龙在测量的药物免疫动力学指标方面相互作用良好，没有动力学改变，但净反应与较强作用药物产生的效应相似或更大。
