Pharmacokinetics and pharmacodynamics of codeine in end-stage renal disease

The pharmacokinetics and pharmacodynamics of codeine and its metabolites codeine glucuronide, morphine, and morphine glucuronide were assessed after the administration of a single 60 mg oral dose of codeine sulfate and a single 60 mg intravenous dose of codeine phosphate in six healthy volunteers and six patients on chronic hemodialysis. Plasma and urine drug and metabolite concentrations were determined by sensitive and specific RIA procedures. Pharmacodynamics were assessed by pupillometry and vital sign determinations. Codeine elimination half-life and mean residence time were increased significantly in the hemodialysis group (18.69 +/- 9.03 hours and 12.77 +/- 7.09 hours, mean +/- SD, respectively) compared with the healthy volunteer group (4.04 +/- 0.60 hours and 3.90 +/- 0.52 hours, respectively). The total body clearance and volume of distribution of codeine were not significantly different between groups. Peak concentrations, times to peak concentrations, and AUCs for the three metabolites were also not significantly different between the groups, in part as a result of significant interpatient variability in the hemodialysis group. Examination of pupillometry and vital sign data did not reveal clinically significant differences in pharmacodynamics between the groups. Adjustment of dosage regimen may be required in some patients with uremia receiving multiple-dose codeine therapy.