Pharmacokinetics and saturable renal tubular secretion of zidovudine in rats

J Pharm Sci. 1989 Jul;78(7):530-4. doi: 10.1002/jps.2600780704.

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 0.76 h at a dose of 10 mg/kg to 1.58 h 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.(ABSTRACT TRUNCATED AT 250 WORDS)

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Blood Proteins / metabolism
  • Chromatography, High Pressure Liquid
  • Kidney Tubules / metabolism*
  • Male
  • Protein Binding
  • Rats
  • Rats, Inbred Strains
  • Zidovudine / metabolism
  • Zidovudine / pharmacokinetics*

Substances

  • Blood Proteins
  • Zidovudine