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

Abstract

AIMA 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. METHODSPopulation 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. RESULTSPopulation 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 ). In contrast, there was no difference in clearance to paracetamol sulphate. CONCLUSIONThe 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. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• In adults, paracetamol is almost exclusively metabolized by the hepatic route and excreted into urine, with paracetamol glucuronide (47-62%) and paracetamol sulphate (25-36%) as the main metabolites. Between 8-10% of the paracetamol dose is oxidized by cytochrome P450 (CYP2E1) into 3-hydroxy-paracetamol and the toxic metabolite N-acetyl-p-benzoquinone-imine (NAPQI), while only 1-4% is excreted in urine as unchanged paracetamol.• Total clearance of paracetamol appears higher at Caesarean delivery compared with healthy female volunteers but it is unknown which pathways are affected. WHAT THIS STUDY ADDS• Population pharmacokinetic modelling showed a substantially higher paracetamol clearance in women at delivery compared with a subset of the same women 12 weeks post-partum.• The increase in total paracetamol clearance at delivery is due to a disproportional increase in glucuronidation clearance and a proportional increase in clearance of unchanged paracetamol and in oxidation clearance.• Compared with modelling based on metabolite fractions retrieved in urine only, population modelling based on both plasma and urine collections was of added value to gain insight into how different metabolic pathways of paracetamol contribute to changes in total clearance.

Estradiol and Weight Are Covariates of Paracetamol Clearance in Young Women

“…This is in line with in vivo observations in humans, since compound-specific studies (e.g. lamotrigine, propofol and paracetamol, all undergoing glucuronidation) show raised metabolic drug clearance during pregnancy [6,7,8]. …”

“…Physicians should be aware that the analgesic effect of paracetamol will be shorter in pregnant women or in any setting of raised estradiol levels. However, before higher paracetamol doses are considered to compensate for this, we would like to refer to the recently published evidence that the higher paracetamol clearance during pregnancy is due to a disproportional increase in glucuronidation clearance and a proportional increase in clearance of unchanged paracetamol and in oxidation clearance [7]. It is likely that the latter limits further dose increase in this patient group.…”

Evaluation of changes in oral drug absorption in preterm and term neonates for Biopharmaceutics Classification System (BCS) class I and II compounds

“…Paracetamol There are a number of paediatric popPK models for paracetamol published in the literature, which range from simple one compartment models to more complex three compartment models [31][32][33]. The model by Anderson et al [7], which contains the maturation function introduced in Equation [1], is a one compartment model.…”

Human Placental Lactogen Induces CYP2E1 Expression via PI 3-Kinase Pathway in Female Human Hepatocytes

“…CYP2E1 plays a major role in metabolizing acetaminophen (a commonly used analgesic during pregnancy) to N-acetyl-p-benzoquinone, the toxic metabolite causing fatal liver injury (Lee et al, 1996). Of note, a recent study demonstrated that acetaminophen elimination to oxidative metabolites was significantly increased in women at delivery compared with that in postpartum women, suggesting clinically relevant increase in CYP2E1 expression and/or activity during pregnancy (Kulo et al, 2013). Taken together, caution should be advised when acetaminophen is prescribed to pregnant women.…”