Paracetamol pharmacokinetics and metabolism in young women

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.

Fig. 1

Schematic representation of the pharmacokinetic model and its metabolites in plasma and urine [Abbreviations: P, paracetamol; P-G, paracetamol-glucuronide; P-S, paracetamol-sulphate; P-U, unchanged paracetamol; V1, volume of the central compartment; V2 and V8, volumes of the peripheral compartment; Q and Q1, inter-compartmental clearances between central and peripheral compartment; k, elimination coefficients]

Fig. 2

Diagnostics plots for the final PK model for a women at delivery, b women in early postpartum and c women in late postpartum and d healthy volunteers including observations vs individual predictions (left) and observations vs population predictions (right) for paracetamol concentrations in plasma (circle, upper panels) and amount of paracetamol-glucuronide (diamond), paracetamol-sulphate (triangle), and unchanged paracetamol (square) in urine (lower panels) as paracetamol equivalents with x = y identity line. The solid symbols indicate women on contraceptives, the open symbols women with no contraceptives. In panel c the group of healthy volunteers on contraceptives (n = 14, Gregoire) are distinguished from women in late postpartum by a triangle down, the healthy volunteers with no contraceptives (n = 8) by symbols plus (circle plus; diamond plus, triangle box and square plus)

Fig. 3

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

Fig. 4

Clearance to paracetamol-glucuronide (CL_P-G, grey, l.h⁻¹), clearance to paracetamol-sulphate (CL_P-S, transparent, l.h⁻¹) and clearance of unchanged paracetamol (CL_P-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 CL_P-S at delivery, oral contraceptives (OC) on CL_P-G in non-pregnant women). The sum reflects the total paracetamol clearance, while the coefficients of variation can be retrieved in Table 2