Department of Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.
Pharmacology. 2010;85(6):319-27. doi: 10.1159/000302725. Epub 2010 May 28.
BACKGROUND/AIMS: Interleukin-12 (IL-12) is a cytokine that plays an important role in cell-mediated immunity and shows great potential as a therapeutic agent for the treatment of tumors and infectious diseases.
We investigated the pharmacokinetics (PK) and pharmacodynamics of recombinant human IL-12 (rhIL-12) and rhIL-12 combined with hepatitis B surface antigen (HB(s)Ag) after administration by subcutaneous (s.c.) injection or intravenous infusion in cynomolgus monkeys.
After s.c. injection of rhIL-12 at doses of 0.15-1.5 microg/kg, the monkey's metabolism showed linear kinetic characteristics. The intramuscular injection of HB(s)Ag vaccine did not affect the pharmacokinetic profile of rhIL-12. In monkeys administered rhIL-12 in a continuous dosing fashion, serum rhIL-12 was undetectable, probably due to the neutralizing effect of anti-rhIL-12 antibodies. In monkeys receiving high-dose s.c. injection of rhIL-12, the T(max) for serum rhIL-12 concentration was 4-8 h, and the T(max) for serum interferon-gamma (IFN-gamma) concentration was 24-72 h. However, in monkeys receiving continuous dosing of rhIL-12, serum IFN-gamma concentration was very low or even undetectable.
We found that the PK of rhIL-12 was dose-dependent and its pharmacological effects appeared after T(max) and lasted much longer than mean retention time.
背景/目的：白细胞介素-12（IL-12）是一种细胞因子，在细胞介导的免疫中发挥重要作用，并显示出作为治疗肿瘤和传染病的治疗剂的巨大潜力。
我们研究了重组人白细胞介素-12（rhIL-12）和 rhIL-12 与乙型肝炎表面抗原（HB(s)Ag）联合给药后通过皮下（s.c.）注射或静脉输注在食蟹猴中的药代动力学（PK）和药效学。
rhIL-12 以 0.15-1.5μg/kg 的剂量皮下注射后，猴子的代谢呈现线性动力学特征。HB(s)Ag 疫苗的肌肉注射不影响 rhIL-12 的药代动力学特征。在连续给予 rhIL-12 的猴子中，血清 rhIL-12 无法检测到，可能是由于抗 rhIL-12 抗体的中和作用。在接受高剂量皮下注射 rhIL-12 的猴子中，血清 rhIL-12 浓度的 T(max)为 4-8 小时，血清干扰素-γ（IFN-γ）浓度的 T(max)为 24-72 小时。然而，在接受 rhIL-12 连续给药的猴子中，血清 IFN-γ浓度非常低或甚至无法检测到。
我们发现 rhIL-12 的 PK 呈剂量依赖性，其药理作用在 T(max)后出现，并持续时间远远长于平均滞留时间。
