Center for Clinical Pharmacology, University Hospitals Leuven, Leuven, Belgium.
Br J Clin Pharmacol. 2013 Mar;75(3):850-60. doi: 10.1111/j.1365-2125.2012.04402.x.
A recent report on intravenous (i.v.) paracetamol pharmacokinetics (PK) showed a higher total clearance in women at delivery compared with non-pregnant women. To describe the paracetamol metabolic and elimination routes involved in this increase in clearance, we performed a population PK analysis in women at delivery and post-partum in which the different pathways were considered.
Population PK parameters using non-linear mixed effect modelling were estimated in a two-period PK study in women to whom i.v. paracetamol (2 g loading dose followed by 1 g every 6 h up to 24 h) was administered immediately following Caesarean delivery and in a subgroup of the same women to whom single 2 g i.v.loading dose was administered 10-15 weeks post-partum.
Population PK analysis was performed based on 255 plasma and 71 urine samples collected in 39 women at delivery and in eight of these 39 women 12 weeks post-partum. Total clearance was higher in women at delivery compared with 12th post-partum week (21.1 vs. 11.7 l h⁻¹) due to higher clearances to paracetamol glucuronide (11.6 vs. 4.76 l h⁻¹), to oxidative metabolites (4.95 vs. 2.77 l h⁻¹) and of unchanged paracetamol (1.15 vs. 0.75 l h⁻¹). In contrast, there was no difference in clearance to paracetamol sulphate.
The increased total paracetamol clearance at delivery is caused by a disproportional increase in glucuronidation clearance and a proportional increase in clearance of unchanged paracetamol and in oxidation clearance, of which the latter may potentially limit further dose increase in this patient group.
最近有一份关于静脉内（i.v.）扑热息痛药代动力学（PK）的报告显示，分娩时女性的总清除率高于非孕妇。为了描述导致清除率增加的扑热息痛代谢和消除途径，我们在分娩和产后的女性中进行了群体 PK 分析，其中考虑了不同的途径。
在一项两期 PK 研究中，使用非线性混合效应建模估计了人口 PK 参数，该研究在接受剖宫产的女性中立即给予静脉内扑热息痛（2g 负荷剂量，然后每 6 小时给予 1g，持续 24 小时），并在同一组女性中的亚组中给予单次 2g 静脉内负荷剂量，在产后 10-15 周给予。
在 39 名分娩时的女性和其中 39 名女性中的 8 名产后 12 周时采集了 255 个血浆和 71 个尿液样本进行了群体 PK 分析。与产后第 12 周相比，分娩时的总清除率更高（21.1 比 11.7 l·h⁻¹），这是由于对扑热息痛葡萄糖醛酸（11.6 比 4.76 l·h⁻¹）、对氧化代谢物（4.95 比 2.77 l·h⁻¹）和未变化的扑热息痛（1.15 比 0.75 l·h⁻¹）的清除率更高所致。相比之下，对扑热息痛硫酸盐的清除率没有差异。
分娩时总扑热息痛清除率的增加是由于葡萄糖醛酸化清除率的不成比例增加和未变化的扑热息痛和氧化清除率的比例增加所致，其中后者可能限制了该患者群体进一步增加剂量。
