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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

Clearance to paracetamol-glucuronide (CLP-G, grey, l.h−1), clearance to paracetamol-sulphate (CLP-S, transparent, l.h−1) and clearance of unchanged paracetamol (CLP-U, striped, l.h−1) as estimated at delivery, in early postpartum, or in late postpartum/healthy volunteers are provided with the impact of the other covariates (preterm on CLP-S at delivery, oral contraceptives (OC) on CLP-G in non-pregnant women). The sum reflects the total paracetamol clearance, while the coefficients of variation can be retrieved in Table 2
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Fig4: Clearance to paracetamol-glucuronide (CLP-G, grey, l.h−1), clearance to paracetamol-sulphate (CLP-S, transparent, l.h−1) and clearance of unchanged paracetamol (CLP-U, striped, l.h−1) as estimated at delivery, in early postpartum, or in late postpartum/healthy volunteers are provided with the impact of the other covariates (preterm on CLP-S at delivery, oral contraceptives (OC) on CLP-G in non-pregnant women). The sum reflects the total paracetamol clearance, while the coefficients of variation can be retrieved in Table 2

Mentions: The current study explored the variability in the different metabolic and elimination clearance estimates in young women following iv paracetamol administration. To allow for an analysis of the different metabolic pathways, we applied an earlier described model, based on simultaneous collection of plasma and urine [16]. Using this approach, we clearly confirmed the significantly higher (Factor = 2.03, 15.8 l.h−1) clearance to paracetamol glucuronide at delivery and significantly lower (Factor = 0.55, 4.66 l.h−1) clearance in early postpartum when compared to healthy female volunteers (7.33 l.h−1) [11, 16]. In addition, the use of oral contraceptives (Factor = 1.46) – obviously limited to non-pregnant women - was also found to affect clearance to paracetamol glucuronide. Besides these major effects on paracetamol metabolic clearance, there was a minor impact of preterm (Factor = 1.34), but not for term delivery on clearance to paracetamol sulphate and of the urine flow on elimination of unchanged paracetamol in urine (Fig. 4). Finally, these clinical covariates performed better as predictors of altered paracetamol glucuronidation clearance when compared to oestradiol or progesterone levels.Fig. 4


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)

Clearance to paracetamol-glucuronide (CLP-G, grey, l.h−1), clearance to paracetamol-sulphate (CLP-S, transparent, l.h−1) and clearance of unchanged paracetamol (CLP-U, striped, l.h−1) as estimated at delivery, in early postpartum, or in late postpartum/healthy volunteers are provided with the impact of the other covariates (preterm on CLP-S at delivery, oral contraceptives (OC) on CLP-G in non-pregnant women). The sum reflects the total paracetamol clearance, while the coefficients of variation can be retrieved in Table 2
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig4: Clearance to paracetamol-glucuronide (CLP-G, grey, l.h−1), clearance to paracetamol-sulphate (CLP-S, transparent, l.h−1) and clearance of unchanged paracetamol (CLP-U, striped, l.h−1) as estimated at delivery, in early postpartum, or in late postpartum/healthy volunteers are provided with the impact of the other covariates (preterm on CLP-S at delivery, oral contraceptives (OC) on CLP-G in non-pregnant women). The sum reflects the total paracetamol clearance, while the coefficients of variation can be retrieved in Table 2
Mentions: The current study explored the variability in the different metabolic and elimination clearance estimates in young women following iv paracetamol administration. To allow for an analysis of the different metabolic pathways, we applied an earlier described model, based on simultaneous collection of plasma and urine [16]. Using this approach, we clearly confirmed the significantly higher (Factor = 2.03, 15.8 l.h−1) clearance to paracetamol glucuronide at delivery and significantly lower (Factor = 0.55, 4.66 l.h−1) clearance in early postpartum when compared to healthy female volunteers (7.33 l.h−1) [11, 16]. In addition, the use of oral contraceptives (Factor = 1.46) – obviously limited to non-pregnant women - was also found to affect clearance to paracetamol glucuronide. Besides these major effects on paracetamol metabolic clearance, there was a minor impact of preterm (Factor = 1.34), but not for term delivery on clearance to paracetamol sulphate and of the urine flow on elimination of unchanged paracetamol in urine (Fig. 4). Finally, these clinical covariates performed better as predictors of altered paracetamol glucuronidation clearance when compared to oestradiol or progesterone levels.Fig. 4

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