U. Martin et al., THE DISPOSITION OF PARACETAMOL AND ITS CONJUGATES DURING MULTIPLE DOSING IN PATIENTS WITH END-STAGE RENAL-FAILURE MAINTAINED ON HEMODIALYSIS, European Journal of Clinical Pharmacology, 45(2), 1993, pp. 141-145
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 cle
arance < 5 ml x min-1) maintained on haemodialysis 2 or 3 times per we
ek. 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 da
ys samples were taken at the start of the session. The mean plasma con
centration of paracetamol was 6.8 mg x l-1 after the first 24 h and su
bsequently varied little throughout the 10 days. Apparent steady-state
plasma concentrations of 60.0 mg x l-1 and 54.5 mg x l-1 were reached
for the glucuronide and sulphate conjugate of paracetamol respectivel
y by the 2nd day of treatment with little variation throughout the rem
ainder of the study. These steady-state concentrations of paracetamol
glucuronide and sulphate were much lower than predicted. The steady-st
ate plasma concentrations of the retained cysteine and mercapturate co
njugates of paracetamol were low (5.7 and 3.7 mg x l-1, respectively)
and there was no evidence of accumulation of these potentially toxic m
etabolites. It is not clear why regular dosing with paracetamol in hae
modialysis patients did not cause the accumulation of paracetamol gluc
uronide or sulphate as predicted. There may be enterohepatic eliminati
on of retained paracetamol conjugates or depletion of substrates such
as inorganic sulphate during chronic dosing.