The disposition of paracetamol and the accumulation of its glucuronide and sulphate conjugates during multiple dosing in patients with chronic renal failure

Summary

We have compared the disposition of oral paracetamol (1.0 g t.d.s. for 10 days) in 6 healthy volunteers and 6 conservatively-managed patients with chronic renal failure (mean plasma creatinine 451 μmol·l⁻¹). Blood was sampled daily for 10 days before the morning dose of paracetamol.

Each day the pretreatment plasma concentrations of paracetamol were higher in the renal failure patients than in the volunteers, with mean values over the 10 days of 3.1 and 1.1 mg·l⁻¹ respectively. The mean daily plasma concentrations of the sulphate and glucuronide conjugates of paracetamol were markedly higher in the renal failure group and apparent steady-state concentrations of about 25 and 85 mg·1⁻¹ were reached on the 2nd and 6th days respectively. The mean steady-state plasma concentrations of the glucuronide conjugate on the 7th to 10th days of treatment were positively correlated with the plasma creatinine concentration (r=0.97), but this relationship did not hold for the sulphate conjugate. Cysteine and mercapturate conjugates could only be detected in one patient.

Predictions of steady-state concentrations based on previous studies with single doses of paracetamol in renal failure patients were remarkably accurate for the glucuronide but not for the sulphate conjugate.

These results are consistent with some extra-renal elimination of retained paracetamol conjugates in patients with chronic renal failure, with limited regeneration of the parent compound. The sulphate metabolite did not accumulate as predicted, possibly because of depletion of inorganic sulphate.