The disposition of paracetamol and its conjugates during multiple dosing in patients with end-stage renal failure maintained on haemodialysis

Summary

The disposition of oral paracetamol (1.0 g 3 times daily for 10 days) was studied in 6 patients with end-stage renal failure (creatinine clearance <5 ml×min⁻¹) maintained on haemodialysis 2 or 3 times per week. Blood was sampled daily for 10 days. The time of sampling depended on whether the patients were dialysed in the morning or afternoon but was always within 5 h of the last dose of paracetamol. On dialysis days samples were taken at the start of the session.

The mean plasma concentration of paracetamol was 6.8mg× 1⁻¹ after the first 24 h and subsequently varied little throughout the 10 days. Apparent steady-state plasma concentrations of 60.0 mg×1⁻¹ and 54.5 mg×1⁻¹ were reached for the glucuronide and sulphate conjugate of paracetamol respectively by the 2nd day of treatment with little variation throughout the remainder of the study. These steady-state concentrations of paracetamol glucuronide and sulphate were much lower than predicted. The steady-state plasma concentrations of the retained cysteine and mercapturate conjugates of paracetamol were low (5.7 and 3.7 mg×1⁻¹, respectively) and there was no evidence of accumulation of these potentially toxic metabolites.

It is not clear why regular dosing with paracetamol in haemodialysis patients did not cause the accumulation of paracetamol glucuronide or sulphate as predicted. There may be enterohepatic elimination of retained paracetamol conjugates or depletion of substrates such as inorganic sulphate during chronic dosing.