Paracetamol pharmacokinetics and metabolism in young women

Abstract

BackgroundThere is relevant between individual variability in paracetamol clearance in young women. In this pooled study, we focused on the population pharmacokinetic profile of intravenous paracetamol metabolism and its covariates in young women.MethodsPopulation PK parameters using non-linear mixed effect modelling were estimated in a pooled dataset of plasma and urine PK studies in 69 young women [47 at delivery, 8/47 again 10–15 weeks after delivery (early postpartum), and 7/8 again 1 year after delivery (late postpartum), 22 healthy female volunteers with or without oral contraceptives].ResultsPopulation PK parameters were estimated based on 815 plasma samples and 101 urine collections. Compared to healthy female volunteers (reference group) not on oral contraceptives, being at delivery was the most significant covariate for clearance to paracetamol glucuronide (Factor = 2.03), while women in early postpartum had decreased paracetamol glucuronidation clearance (Factor = 0.55). Women on contraceptives showed increased paracetamol glucuronidation clearance (Factor = 1.46). The oestradiol level did not further affect this model. Being at delivery did not prove significant for clearance to paracetamol sulphate, but was higher in pregnant women who delivered preterm (<37 weeks, Factor = 1.34) compared to term delivery and non-pregnant women. Finally, clearance of unchanged paracetamol was dependent on urine flow rate.ConclusionsCompared to healthy female volunteers not on oral contraceptives, urine paracetamol glucuronidation elimination in young women is affected by pregnancy (higher), early postpartum (lower) or exposure to oral contraceptives (higher), resulting in at least a two fold variability in paracetamol clearance in young women.

Integration of Placental Transfer in a Fetal–Maternal Physiologically Based Pharmacokinetic Model to Characterize Acetaminophen Exposure and Metabolic Clearance in the Fetus

“…In brief, first, a PBPK model was previously developed for both intravenous and oral acetaminophen administration in non-pregnant women. The predictive performance of the model was evaluated by comparing simulations with observed in vivo pharmacokinetic profiles of acetaminophen, acetaminophen-glucuronide, acetaminophen-sulphate, and unchanged acetaminophen after both oral and intravenous acetaminophen administration of standard dosages [20][21][22]. Once the non-pregnant PBPK model captured the observed pharmacokinetics adequately, all drug-specific parameters were fixed and pregnancy-specific changes were incorporated.…”

“…Once the non-pregnant PBPK model captured the observed pharmacokinetics adequately, all drug-specific parameters were fixed and pregnancy-specific changes were incorporated. Model performance was evaluated by comparing simulations with observed in vivo pharmacokinetic profiles of acetaminophen, acetaminophenglucuronide, acetaminophen-sulphate, and unchanged acetaminophen obtained from third-trimester pregnant women [20]. For more detailed information about parameterization and validation of the previously developed pregnancy PBPK model we refer to Mian et al [17].…”

Physiologically Based Pharmacokinetic Modeling to Characterize Acetaminophen Pharmacokinetics and N-Acetyl-p-Benzoquinone Imine (NAPQI) Formation in Non-Pregnant and Pregnant Women

“…Regarding the plasma concentration-time profiles of oral acetaminophen 1000 mg in non-pregnant and pregnant populations (ESM_2A), maximum concentration (C max ) values were higher in non-pregnant women and decreased with increasing duration of gestational week, while the AUC from time zero to 6 h (AUC 0-6h ) decreased with increasing duration of gestational age. Regarding the plasma concentration-time profiles of NAPQI after administration of oral [31] acetaminophen plasma concentration-time profiles (left) and predicted and observed [31] acetaminophen inactive metabolites urine concentration-time profiles (right) in populations of a non-pregnant women after administration of intravenous acetaminophen 2000 mg and b third trimester pregnant women after administration of an intravenous acetaminophen 2000 mg loading dose followed by 1000 mg every 6 h. For the inactive metabolites, orange, pink, and green indicate acetaminophen glucuronide, acetaminophen sulfate, and unchanged acetaminophen in urine concentrations, respectively. The shaded area denotes the predicted 95% confidence interval.…”

“…Following oral administration of acetaminophen 1000 mg, the predicted C ss,avg (median [interquartile range, IQR]) was 6.7 Goodness-of-fit plot (predicted concentration versus observed concentration) for acetaminophen and its metabolites (acetaminophen unchanged, acetaminophen glucuronide, acetaminophen sulfate). For non-pregnant women, observed acetaminophen data were taken from Allegaert et al [31], Mitchell et al [34], and Beaulac-Baillargeon and Rocheleau [33]; for pregnant women, observed acetaminophen, acetaminophen glucuronide, and acetaminophen sulfate data were taken from Allegaert et al [31] and Beaulac-Baillargeon and Rocheleau [33]. The solid line denotes the line of identity.…”

“…Observed PK parameters for acetaminophen for both non-pregnant and pregnant women following oral administration of 650 mg are taken from Beaulac-Baillargeon and Rocheleau [33] and those following intravenous administration of 2000 mg from Allegaert et al [31]. Data are expressed as mean AUC ∞ area under the plasma concentration-time curve from time zero to infinity, CL clearance, C max maximum concentration, F bioavailability, PK pharmacokinetic, mg/L in non-pregnant women and in the first, second, and third trimester of pregnancy, respectively (Fig.…”