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Paracetamol pharmacokinetics and metabolism in young women.

Allegaert K, Peeters MY, Beleyn B, Smits A, Kulo A, van Calsteren K, Deprest J, de Hoon J, Knibbe CA - BMC Anesthesiol (2015)

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

Affiliation: NICU, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium. karel.allegaert@uzleuven.be.

ABSTRACT

Background: There 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.

Methods: Population 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].

Results: Population 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.

Conclusions: Compared 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.

No MeSH data available.


Related in: MedlinePlus

Model based simulation of plasma paracetamol disposition after 2 g loading dose, followed by 1 g paracetamol every 6 h in women with different clinical characteristics [at delivery (a, circle), in early postpartum (b, triangle), in late postpartum or in healthy volunteers (c, cube)]. For the b and c panel, simulations are provided with (white) or without (black) exposure to oral contraceptives
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Fig3: Model based simulation of plasma paracetamol disposition after 2 g loading dose, followed by 1 g paracetamol every 6 h in women with different clinical characteristics [at delivery (a, circle), in early postpartum (b, triangle), in late postpartum or in healthy volunteers (c, cube)]. For the b and c panel, simulations are provided with (white) or without (black) exposure to oral contraceptives

Mentions: Central volume standardized for body weight significantly improved the model. However, being at delivery as a covariate for the central volume proved to be more significant. Addition of body weight on central volume for the different groups did not further improve the model. The inter-compartmental clearance (Q) standardized for body weight (BW) proved significant. The inter-compartmental clearance Q1 was reduced in women in early postpartum (Factor = 0.13) relative to the population mean of 61.1. (ΔOF = 46.6 backward deletion vs final model). The group late postpartum could not be identified as significant covariate, which would suggest that the pharmacokinetics 1 year postpartum equals the healthy volunteer group. The impact of these covariates (pregnancy, early/late postpartum, volunteers, with or without oral contraceptives) on plasma paracetamol disposition is illustrated in Fig. 3.Fig. 3


Paracetamol pharmacokinetics and metabolism in young women.

Allegaert K, Peeters MY, Beleyn B, Smits A, Kulo A, van Calsteren K, Deprest J, de Hoon J, Knibbe CA - BMC Anesthesiol (2015)

Model based simulation of plasma paracetamol disposition after 2 g loading dose, followed by 1 g paracetamol every 6 h in women with different clinical characteristics [at delivery (a, circle), in early postpartum (b, triangle), in late postpartum or in healthy volunteers (c, cube)]. For the b and c panel, simulations are provided with (white) or without (black) exposure to oral contraceptives
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4644344&req=5

Fig3: Model based simulation of plasma paracetamol disposition after 2 g loading dose, followed by 1 g paracetamol every 6 h in women with different clinical characteristics [at delivery (a, circle), in early postpartum (b, triangle), in late postpartum or in healthy volunteers (c, cube)]. For the b and c panel, simulations are provided with (white) or without (black) exposure to oral contraceptives
Mentions: Central volume standardized for body weight significantly improved the model. However, being at delivery as a covariate for the central volume proved to be more significant. Addition of body weight on central volume for the different groups did not further improve the model. The inter-compartmental clearance (Q) standardized for body weight (BW) proved significant. The inter-compartmental clearance Q1 was reduced in women in early postpartum (Factor = 0.13) relative to the population mean of 61.1. (ΔOF = 46.6 backward deletion vs final model). The group late postpartum could not be identified as significant covariate, which would suggest that the pharmacokinetics 1 year postpartum equals the healthy volunteer group. The impact of these covariates (pregnancy, early/late postpartum, volunteers, with or without oral contraceptives) on plasma paracetamol disposition is illustrated in Fig. 3.Fig. 3

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

Affiliation: NICU, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium. karel.allegaert@uzleuven.be.

ABSTRACT

Background: There 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.

Methods: Population 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].

Results: Population 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.

Conclusions: Compared 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.

No MeSH data available.


Related in: MedlinePlus