TOXICOLOGY The comparative pharmacokinetics of modified-release and immediate-release paracetamol in a simulated overdose model Angela Chiew, 1 Peter Day, 2 Chris Salonikas, 2 Daya Naidoo 2 , Andis Graudins 3 and Rebecca Thomas 2 1 Clinical and Experimental Toxicology Unit, Department of Emergency Medicine, Prince of Wales Hospital, 2 South Eastern Area Laboratory Services (SEALS Pathology), Prince of Wales Hospital Campus, Randwick, New South Wales, and 3 Southern Clinical School, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia 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 paraceta- mol (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 elimi- nation half-life (t 1/2 ) were compared. Results: PEx exhibited significantly lower paracetamol Cmax (252.33 mmol/L vs 565.56 mmol/L, P = 0.0421), AUC (0–•) (2133 mmol/h/L vs 2637 mmol/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 prepa- rations, PEx vs APAP-IR, showed similar AUC (0–•) (1369 mmol/h/L vs 1089 mmol/h/L), Tmax (3.889 h vs 4.444 h), Cmax (95.889 mmol/L vs 95.889 mmol/L) and t 1/2 (3.895 h vs 3.810 h). Glucuronide metabolite concentrations revealed that PEx produced a lower Cmax (257.44 mmol/L vs 335.22 mmol/L, P = 0.0239) than APAP-IR. All other pharmacokinetic parameters were similar. Cysteine metabolite was not detected. Correspondence: Dr Angela Chiew, Department of Emergency Medicine, Prince of Wales Hospital, Barker Street, Randwick, NSW 2031, Australia. Email: a_chiew@hotmail.com Angela Chiew, BSci(Med), MB BS(Hons), Toxicology Fellow and Emergency Registrar; Peter Day, BSc (Hons) MSc, DipMT, Senior Hospital Scientist; Chris Salonikas, MAppSc, Senior Hospital Scientist; Daya Naidoo, M.D., FRCPA., MAACB, Former Director of Clinical Chemistry; Andis Graudins, MB BS(Hons), PhD, FACEM, FACMT, Professor; Rebecca Thomas, BSc, MSc student in Toxicology, Hospital Scientist. doi: 10.1111/j.1742-6723.2010.01354.x Emergency Medicine Australasia (2010) 22, 548–555 © 2010 The Authors EMA © 2010 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine