title: The comparative pharmacokinetics of modified-release and immediate-release paracetamol in a simulated overdose model.
abstract: BACKGROUND
  Panadol Extend (PEx) is an over-the-counter, modified-release formulation of paracetamol. Each 665 mg tablet contains 69% slow-release and 31% immediate-release paracetamol. In simulated human overdose, PEx exhibits lower and later peak serum concentrations and a lower area-under-the-curve (AUC) than comparable doses of immediate-release paracetamol (APAP-IR). The lower AUC might result from incomplete absorption of paracetamol or simultaneous metabolism with absorption.
  
  
  OBJECTIVE
  Do differences in pharmacokinetics (PK) between PEx and APAP-IR result from incomplete absorption or simultaneous absorption and metabolism of paracetamol?
  
  
  METHODS
  Cross-over study of 80 mg/kg of PEx or APAP-IR in nine volunteers. Serial plasma paracetamol, glucuronide, sulphate and cysteine metabolite estimates performed over 24 h. Peak plasma concentration (Cmax), AUC((0-∞),) time to peak concentration (Tmax) and elimination half-life (t(1/2) ) were compared.
  
  
  RESULTS
  PEx exhibited significantly lower paracetamol Cmax (252.33 µmol/L vs 565.56 µmol/L, P= 0.0421), AUC((0-∞)) (2133 µmol/h/L vs 2637 µmol/h/L, P= 0.0004) and delayed Tmax (2.889 h vs 1.389 h, P= 0.0189) than APAP-IR. Sulphate metabolite PK parameters for both preparations, PEx vs APAP-IR, showed similar AUC((0-∞)) (1369 µmol/h/L vs 1089 µmol/h/L), Tmax (3.889 h vs 4.444 h), Cmax (95.889 µmol/L vs 95.889 µmol/L) and t(1/2) (3.895 h vs 3.810 h). Glucuronide metabolite concentrations revealed that PEx produced a lower Cmax (257.44 µmol/L vs 335.22 µmol/L, P= 0.0239) than APAP-IR. All other pharmacokinetic parameters were similar. Cysteine metabolite was not detected.
  
  
  CONCLUSIONS
  There were minor differences between the PK parameters of the two major paracetamol metabolites of these two preparations in simulated overdose. The variability in paracetamol AUC seen between the two preparations in moderate overdose might be explained by concurrent metabolism of paracetamol during slower absorption with PEx.
authors.affiliation: Clinical and Experimental Toxicology Unit, Department of Emergency Medicine, Prince of Wales Hospital, Barker Street, Randwick, New South Wales 2031, Australia. a_chiew@hotmail.com
authors.forename: Angela
authors.initials: A
authors.lastname: Chiew
authors.forename: Peter
authors.initials: P
authors.lastname: Day
authors.forename: Chris
authors.initials: C
authors.lastname: Salonikas
authors.forename: Daya
authors.initials: D
authors.lastname: Naidoo
authors.forename: Andis
authors.initials: A
authors.lastname: Graudins
authors.forename: Rebecca
authors.initials: R
authors.lastname: Thomas
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects / Q000493:pharmacokinetics*; D000328:Adult; D018712:Analgesics, Non-Narcotic / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001315:Australia; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D008954:Models, Biological; D004366:Nonprescription Drugs / Q000009:adverse effects / Q000493:pharmacokinetics*; D063487:Prescription Drug Misuse
chemical_list: D018712:Analgesics, Non-Narcotic; D003692:Delayed-Action Preparations; D004366:Nonprescription Drugs; D000082:Acetaminophen