[Pharmacokinetics of zidovudine (AZT) and its metabolite (G-AZT) in healthy subjects and in patients with kidney failure]. / Pharmacocinétique de la zidovudine (AZT) et de son métabolite (G.AZT) chez le sujet sain et l'insuffisant rénal.

Pharmacokinetics of zidovudine was investigated after oral administration (200 mg) in 25 HIV seronegative subjects: 14 patients with severe renal impairment (creatinine clearance 6 to 31 ml/min), 5 hemodialyzed anuric patients, and 6 healthy subjects. In healthy subjects, G. AZT concentrations are higher than those of AZT; AUC were 23.7 +/- 1.9 and 5.2 +/- 0.6 mumol.h/l respectively. Formation of G. AZT rate-limits its elimination: G. AZT half-life parallels that of AZT which is around 1 hour. In uremic patients AZT concentrations are moderately increased (AUC = 11.7 +/- 1.1 mumol.h/l), whereas half-life and MRT remains unchanged, despite the decreased renal clearance (16 +/- 2 vs 220 +/- 58 ml/min). In contrast G. AZT concentrations are markedly increased (AUC = 403 +/- 89 mumol.h/l). As a consequence of the decreased renal clearance (27 +/- 3 vs 331 +/- 42 ml/min), elimination is the rate limiting step and half-life is increased (8 +/- 2 vs 0.9 +/- 0.1 h). Contribution of a 4-hour hemodialysis session to AZT elimination appears negligible whereas elimination of G. AZT is enhanced.

Zidovudine disposition in patients with severe renal impairment: influence of hemodialysis.

Pharmacokinetics of zidovudine (azidothymidine, AZT) was investigated after oral administration (200 mg) in 25 HIV seronegative subjects: 14 patients with severe renal impairment (creatinine clearance 6 to 31 ml/min), five hemodialyzed anuric patients, and six healthy subjects. Plasma and urine concentrations of zidovudine and its glucuronidated metabolite (GAZT) were measured simultaneously by HPLC assay. In healthy subjects, GAZT concentrations were higher than those of AZT; AUC values were 23.7 +/- 1.9 and 5.2 +/- 0.6 mumol.hr/L, respectively. Formation of GAZT rate-limits its elimination: GAZT half-life (t 1/2) parallels that of AZT, which is around 1 hour. In uremic patients, AZT concentrations were moderately increased (AUC = 11.7 +/- 1.1 mumol.hr/L), whereas t 1/2 and mean residence time (MRT) remain unchanged despite the decreased renal clearance (16 +/- 2 versus 220 +/- 58 ml/min) and decreased urinary excretion (1.6 +/- 0.3 versus 8.1 +/- 1.0% of the dose). In contrast, GAZT concentrations are markedly increased (AUC = 402.9 +/- 88.6 mumol.hr/L). As a consequence of the decreased renal clearance (27 +/- 3 versus 331 +/- 42 ml/min), elimination is the rate-limiting step and t 1/2 is increased (8 +/- 2 versus 0.9 +/- 0.1 hr). Contribution of a 4-hour hemodialysis session to AZT elimination appears to be negligible, whereas elimination of GAZT is enhanced. On the sole basis of AZT pharmacokinetic data, no particular dose adjustment appears to be necessary in patients who have severe renal impairment (creatinine clearance between 10 and 30 ml/min). However, high levels of GAZT should be anticipated with the usual dosage regimen.