Pharmacokinetics and saturable renal tubular secretion of zidovudine in rats

Abstract

The purpose of this study was to assess the effects of dose on the pharmacokinetics of zidovudine (3′-azido-3′-deoxythymidine; AZT) in rats. Zidovudine (AZT) was administered intravenously at doses of 10, 50, 100, and 250 mg/kg. Plasma and urine AZT concentrations were determined by HPLC. Plasma AZT concentrations declined rapidly with a terminal half-life ranging from 0.76h at a dose of 10 mg/kg to 1.58h at 250 mg/kg. Total clearance (CLT) was similar at the doses of 10 and 50 mg/kg, with values of 2.80 and 2.73 L/h/kg, respectively. However, there was a trend toward nonlinearity at the dose of 100 mg/kg (CLT = 2.13 L/h/kg) and a significant decrease in CLT (1.22 L/h/kg) at the dose of 250 mg/kg. Nonrenal clearance remained unaffected by dose with a mean value of 0.98 L/h/kg. Renal clearance (CLR) was similar at the doses of 10 and 50 mg/kg, with values of 1.89 and 1.37 L/h/kg, respectively. However, significant decreases in CLR were observed at the doses of 100 (CLR = 1.30 L/h/kg) and 250 mg/kg (CLR = 0.57 L/h/kg). The maximum transport capacity (Tmax) and the Michaelis-Menten constant (Km) for renal tubular secretion obtained after simultaneously fitting plasma concentration—time profiles at the four doses to a renal clearance model were 215.5 ± 82.1 mg/h and 119.3 ± 80.5 mg/L, respectively, thereby yielding an unbound secretory intrinsic clearance (CLus,int) of 1.81 L/h. The high Tmax and Km values account for the high CLR of AZT and explain the linearity of CLR over a wide range of AZT plasma concentrations. Active tubular secretion of AZT, however, is saturable at very high AZT concentrations, resulting in decreased CLR and, thus, CLT at higher doses. The steady-state volume of distribution (Vdss) was similar at the doses of 10 and 50 mg/kg (1.57 and 1.66 L/kg, respectively). There was a pattern towards decrease in Vdss at the dose of 100 mg/kg (Vdss = 1.17 L./kg) and a significant decrease at the dose of 250 mg/kg (Vdss = 0.81 L/kg) suggesting saturable tissue uptake or binding. Thus, the pharmacokinetics of AZT behaves linearly at low doses, but becomes dose dependent as the dose is further increased.