Drugs in Pregnancy and Lactation
Pharmacokinetics of paracetamol and its metabolites in women at delivery and post-partum
Article first published online: 5 FEB 2013
© 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society
British Journal of Clinical Pharmacology
Special Issue: Nutraceuticals Themed Section
Volume 75, Issue 3, pages 850–860, March 2013
How to Cite
Kulo, A., Peeters, M. Y., Allegaert, K., Smits, A., de Hoon, J., Verbesselt, R., Lewi, L., van de Velde, M. and Knibbe, C. A. J. (2013), Pharmacokinetics of paracetamol and its metabolites in women at delivery and post-partum. British Journal of Clinical Pharmacology, 75: 850–860. doi: 10.1111/j.1365-2125.2012.04402.x
- Issue published online: 5 FEB 2013
- Article first published online: 5 FEB 2013
- Accepted manuscript online: 30 JUL 2012 09:56PM EST
- Manuscript Accepted: 24 JUL 2012
- Manuscript Received: 29 MAR 2012
- Fund for Scientific Research
- Fundamental Clinical Investigatorship. Grant Number: 1800209
- JoinEU-SEE scholarship
- elimination routes;
- i.v. paracetamol;
- population pharmacokinetics;
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.