Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Pharmacology & Pharmacy, acetaminophen, elimination routes, i, v, paracetamol, population pharmacokinetics, post-partum, pregnancy, INTRAVENOUS PARACETAMOL, UDP-GLUCURONOSYLTRANSFERASES, POSTOPERATIVE PAIN, CESAREAN DELIVERY, HUMAN-PREGNANCY, ACETAMINOPHEN, GLUCURONIDATION, PROPACETAMOL, SURGERY, SAFETY, Acetaminophen, Administration, Intravenous, Adult, Analgesics, Non-Narcotic, Delivery, Obstetric, Dose-Response Relationship, Drug, Female, Humans, Metabolic Clearance Rate, Pain, Pain Measurement, Postpartum Period, Pregnancy, 1115 Pharmacology and Pharmaceutical Sciences, 3214 Pharmacology and pharmaceutical sciences

Abstract:

AIM: A recent report on intravenous (i.v.) paracetamol pharmacokinetics (PK) showed a higher total clearance in women at delivery compared with non-pregnant women. To describe the paracetamol metabolic and elimination routes involved in this increase in clearance, we performed a population PK analysis in women at delivery and post-partum in which the different pathways were considered. METHODS: Population PK parameters using non-linear mixed effect modelling were estimated in a two-period PK study in women to whom i.v. paracetamol (2 g loading dose followed by 1 g every 6 h up to 24 h) was administered immediately following Caesarean delivery and in a subgroup of the same women to whom single 2 g i.v.loading dose was administered 10-15 weeks post-partum. RESULTS: Population PK analysis was performed based on 255 plasma and 71 urine samples collected in 39 women at delivery and in eight of these 39 women 12 weeks post-partum. Total clearance was higher in women at delivery compared with 12th post-partum week (21.1 vs. 11.7 l h⁻¹) due to higher clearances to paracetamol glucuronide (11.6 vs. 4.76 l h⁻¹), to oxidative metabolites (4.95 vs. 2.77 l h⁻¹) and of unchanged paracetamol (1.15 vs. 0.75 l h⁻¹). In contrast, there was no difference in clearance to paracetamol sulphate. CONCLUSION: The increased total paracetamol clearance at delivery is caused by a disproportional increase in glucuronidation clearance and a proportional increase in clearance of unchanged paracetamol and in oxidation clearance, of which the latter may potentially limit further dose increase in this patient group.