Anderson B J, Holford N H, Woollard G A, Chan P L
Paediatric Intensive Care Department, Auckland Children's Hospital, New Zealand.
Br J Clin Pharmacol. 1998 Sep;46(3):237-43. doi: 10.1046/j.1365-2125.1998.00780.x.
Paracetamol has a central action for both antipyresis and analgesia. Maximum temperature decrease and peak analgesia are reported at 1-2 h after peak plasma paracetamol concentration. We wished to determine the relationship between plasma and cerebrospinal fluid (CSF) pharmacokinetics in children.
Concentration-time profiles in plasma and CSF after nasogastric paracetamol 40 mg kg(-1) were measured in nine children who had indwelling ventricular drains. Estimation of population pharmacokinetic parameters was made using both a standard two-stage population approach (MKMODEL) and a nonlinear mixed effect model (NONMEM). Results were standardized to a 70 kg person using an allometric power model.
Both approaches gave similar estimates. NONMEM parameter estimates were clearance 10.21 h(-1) (CV 47%), volume of distribution 67.11 (CV 58%) and absorption rate constant 0.77 h(-1) (CV 49%). Cerebrospinal fluid concentrations lagged behind those of plasma. The equilibration half time was 0.72 h (CV 117%). The CSF/plasma partition coefficient was 1.18 (CV 8%).
Higher concentrations in the CSF probably reflect the lower free water volume of plasma. The CSF equilibration half time suggests that CSF kinetics approximate more closely to the effect compartment than plasma, but further time is required for paracetamol to exert its effects. Effect site concentrations equilibrate slowly with plasma. Paracetamol should be given 1-2 h before anticipated pain or fever in children.
对乙酰氨基酚具有解热和镇痛的中枢作用。据报道，在血浆对乙酰氨基酚浓度达到峰值后1 - 2小时出现最大体温下降和镇痛峰值。我们希望确定儿童血浆和脑脊液（CSF）药代动力学之间的关系。
对9名留置脑室引流管的儿童口服40 mg·kg⁻¹对乙酰氨基酚后，测量其血浆和脑脊液中的浓度 - 时间曲线。使用标准的两阶段群体方法（MKMODEL）和非线性混合效应模型（NONMEM）对群体药代动力学参数进行估计。使用异速生长幂模型将结果标准化为70 kg体重的人。
两种方法得到的估计值相似。NONMEM参数估计值为清除率10.21 h⁻¹（变异系数47%）、分布容积67.11（变异系数58%）和吸收速率常数0.77 h⁻¹（变异系数49%）。脑脊液浓度滞后于血浆浓度。平衡半衰期为0.72 h（变异系数117%）。脑脊液/血浆分配系数为1.18（变异系数8%）。
脑脊液中较高的浓度可能反映了血浆中较低的自由水量。脑脊液平衡半衰期表明，脑脊液动力学比血浆更接近效应室，但对乙酰氨基酚发挥其作用还需要更多时间。效应部位浓度与血浆达到平衡的速度较慢。儿童应在预期疼痛或发热前1 - 2小时给予对乙酰氨基酚。
