The pharmacokinetics of a single oral 200 mg dose of
netivudine (1-(beta-D-arabinofuranosyl)-5-(1-propynyl)uracil), a
nucleoside analogue under development for use in varicella zoster virus
infections, were studied in 12
renal failure (RF) subjects (
creatinine clearance 15 +/- 7 mL/min) and 12 age-matched healthy subjects with normal
creatinine clearance. Blood and urine samples were collected up to nine days after
drug administration. Concentrations of
netivudine and of its main metabolite, the
pyrimidine base 5-(1-propynyl)uracil (5 PU), were determined by a specific high performance liquid chromatography assay. The mean peak plasma concentrations of
netivudine, Tmax, and volume of distribution were not significantly affected by RF. The elimination half-life of
netivudine was approximately 15 h in subjects with normal renal function and 60 h in RF patients. Plasma and renal clearances of
netivudine were significantly reduced in RF patients and AUC was three to four times higher in these patients. Cmax and AUC of 5 PU were higher in RF patients, and the half-life was also significantly longer. However, the half-life of this metabolite was much lower than that of the parent compound. Tmax and the lag time were similar in the two groups. There were highly significant correlations for
netivudine and 5 PU between half-life and
creatinine clearance and between renal clearance and
creatinine clearance. These findings suggest that
netivudine dosage may need to be reduced in patients with severe
renal failure, and confirm that formation of the 5 PU is independent of the elimination of
netivudine from plasma.