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.

Aim: Paracetamol clearance differs between pregnant and non-pregnant women and between women with or without specific oral contraceptives (OCs). However, an association between female sex hormones and paracetamol clearance has never been explored. Methods: In total, 49 women at delivery, 8 female control subjects without OC use, historical data of 14 women taking OCs, and 15 postpartum observations with and without OCs were pooled to explore covariates of paracetamol clearance. All received a single intravenous 2-gram paracetamol dose, and blood samples were collected up to 6 h after dosing. High-performance liquid chromatography was used to quantify paracetamol. The area under the curve to time infinity (AUC_0-∞) was determined and clearance (l/h·m²) was calculated by dose/ AUC_0-∞. In addition, estradiol and progesterone were quantified by ELISA with electro-chemiluminescence. Results: Median paracetamol clearance at delivery was significantly higher when compared to postpartum or non-pregnant women (11.9 vs. 6.42 and 8.4 l/h·m², at least p < 0.05), while an association between paracetamol clearance and estradiol was observed (R = 0.494, p < 0.0001). In non-pregnant subjects, there was no impact of OC exposure on paracetamol clearance. Multiple regression revealed a linear association (R_adj = 0.41, p < 0.001) between paracetamol clearance and weight (p = 0.0462) and estradiol (p < 0.0001). Conclusion: Estradiol and weight in part explain the variation in paracetamol clearance in young women.

IntroductionIn this pooled study, we focused on the population pharmacokinetic profile of intravenous paracetamol metabolism and its covariates in young women, including during pregnancy and postpartum.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 one 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 (F=2.03), while women in early postpartum had decreased paracetamol glucuronidation clearance (F=0.55). Women on contraceptives showed increased paracetamol glucuronidation clearance (F=1.46). The oestradiol level did not further affected 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, F=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, the urine paracetamol glucuronidation elimination in young women is affected by pregnancy (higher), early postpartum (lower) or exposure to oral contraceptives (higher). This may be of relevance to predict variability in glucuronidation activity in young women and to predict fetal exposure to paracetamol and its metabolites.