Pharmacokinetics of paracetamol and its metabolites in women at delivery and post-partum

Aim: 

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. 

Methods:

Population PK parameters using non-linear mixed effect modelling were estimated in a two-period PK study in women to whom i.v. paracetamol (2g loading dose followed by 1g every 6h up to 24h) was administered immediately following Caesarean delivery and in a subgroup of the same women to whom single 2g i.v.loading dose was administered 10-15 weeks post-partum. 

Results: 

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 lh^-1) due to higher clearances to paracetamol glucuronide (11.6 vs. 4.76 lh^-1), to oxidative metabolites (4.95 vs. 2.77 lh^-1) and of unchanged paracetamol (1.15 vs. 0.75 lh^-1). In contrast, there was no difference in clearance to paracetamol sulphate.

Conclusion: 

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.