Protein Binding of Zidovudine in the Sera of Healthy Controls and Patients Infected with Human Immunodeficiency Virus

Summary

Zidovudine (ZDV) is widely used in patients with HIV infection. Although major pharmacokinetic parameters have been evaluated with comparable results, the available data so far on the protein binding of ZDV in serum are contradictory. A method for the determination of the unbound drug in sera was used to investigate different experimental conditions possibly affecting the protein binding of ZDV. Protein binding was assessed in ‘spiked’ sera (ZDV 10 μmol/L) from 15 healthy controls as well as in sera from 10 human immunodeficiency virus (HIV)-infected patients on treatment. The protein binding of ZDV was found to be the same in plasma and serum, and was not affected by freezing and subsequent thawing of samples. Protein binding was strongly dependent on pH, and increased from 14.0 ± 0.6% at pH 6.7 to 31.9 ± 4.0% at pH 8.8 (p < 0.05). Furthermore, protein binding was dependent on temperature, and decreased from 17.9 ± 0.7% at room temperature to 10.8 ± 0.4% at 37°C. Protein binding (at room temperature and pH 7.4) was found to be comparable in spiked sera from the healthy volunteers (19.0 ± 0.7%) and in sera from the HIV-infected patients receiving ZDV treatment (18.7 ± 2.3%). Equilibrium binding studies were suggestive of two binding sites with K_dS of 262 ± 72 μmol/L (high affinity) and 3566 ± 785 μmol/L (low affinity), respectively. Assuming physiological conditions, we found that protein binding of ZDV was as low as 11%. This indicates that binding of ZDV to serum proteins contributes only to a minor extent to the pharmacokinetic properties of this drug.