title: Weight, pregnancy and oral contraceptives affect intravenous paracetamol clearance in young women.
abstract: OBJECTIVE
  Because of the extensive variability in paracetamol clearance in young women, published data were pooled with newly collected observations in search of covariates of paracetamol pharmacokinetics (PK) within this specific population.
  
  
  METHODS
  PK estimates and clinical characteristics [pregnant, weight, exposure to oral contraceptives (OC)] in young women following IV loading dose (2 g paracetamol) were pooled, using a non-compartmental linear disposition model in individual time-concentration profiles. Data were reported by median and range. Rank correlation was used to link clearance (l/h) to weight, Mann Whitney U test to compare clearance (l/h.m-2) between subgroups (pregnant, OC exposure). Finally, a multiple regression model with clearance (l/h) in all women and all non-pregnant women was performed.
  
  
  RESULTS
  Based on 73 paracetamol PK estimates, a 8-fold variability in clearance (range 7.1-62.2 l/h) was documented, in part explained by a correlation (r2=0.36) between clearance (l/h) and weight. Clearance (l/h and l/h.m-2) and distribution volume (l) at delivery (n=36) were higher compared to non-pregnant observations. In non-pregnant women, women on OC (n=20) had a higher paracetamol clearance (l/h.m-2) compared to women (n=17) not on OC (p = 0.023). Weight (p = 0.0043) and pregnancy (p = 0.02) were independent variables (r=0.56) of paracetamol clearance (l/h). In non-pregnant women, weight (p = 0.009) and OC exposure (p = 0.03) were independent variables (r=0.51).
  
  
  CONCLUSIONS
  Weight, pregnancy and OC result in higher clearance of IV paracetamol in young women. Besides compound specific relevance, these findings also unveil covariates of drug metabolism in young women.
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences and Center for Clinical Pharmacology, University Hospitals Leuven, Leuven, Belgium. karel.allegaert@uzleuven.be  
authors.forename: A
authors.initials: A
authors.lastname: Kulo
authors.forename: K
authors.initials: K
authors.lastname: Van Calsteren
authors.forename: M
authors.initials: M
authors.lastname: van de Velde
authors.forename: N
authors.initials: N
authors.lastname: Mulabegovic
authors.forename: R
authors.initials: R
authors.lastname: Verbesselt
authors.forename: J N
authors.initials: JN
authors.lastname: de Hoon
authors.forename: J
authors.initials: J
authors.lastname: Verhaeghe
authors.forename: K
authors.initials: K
authors.lastname: Allegaert
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage* / Q000097:blood*; D061605:Administration, Intravenous; D000328:Adult; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000097:blood; D001835:Body Weight / Q000187:drug effects / Q000502:physiology*; D015331:Cohort Studies; D003276:Contraceptives, Oral / Q000008:administration & dosage* / Q000097:blood*; D036861:Delivery, Obstetric; D004347:Drug Interactions / Q000502:physiology; D005260:Female; D006801:Humans; D011247:Pregnancy / Q000097:blood* / Q000187:drug effects; D055815:Young Adult
chemical_list: D018712:Analgesics, Non-Narcotic; D003276:Contraceptives, Oral; D000082:Acetaminophen