title: Pharmacokinetics of paracetamol and its metabolites in women at delivery and post-partum.
abstract: OBJECTIVE
  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 (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.
  
  
  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 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.
  
  
  CONCLUSIONS
  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.
authors: Center for Clinical Pharmacology, University Hospitals Leuven, Leuven, Belgium.
authors: Aida
authors: A
authors: Kulo
authors: Mariska Y
authors: MY
authors: Peeters
authors: Karel
authors: K
authors: Allegaert
authors: Anne
authors: A
authors: Smits
authors: Jan
authors: J
authors: de Hoon
authors: Rene
authors: R
authors: Verbesselt
authors: Liesbeth
authors: L
authors: Lewi
authors: Marc
authors: M
authors: van de Velde
authors: Catherijne A J
authors: CA
authors: Knibbe
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D061605:Administration, Intravenous; D000328:Adult; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D036861:Delivery, Obstetric; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008657:Metabolic Clearance Rate; D010146:Pain / Q000188:drug therapy; D010147:Pain Measurement; D049590:Postpartum Period / Q000378:metabolism*; D011247:Pregnancy
chemical_list: D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen; C037386:acetaminophen glucuronide; C045667:acetaminophen sulfate ester