Human Serum Albumin binding of novel antiretroviral nucleoside derivativesof AZT

The binding of novel nucleoside derivatives (2-7) to the Human Serum Albumi n (HSA) was studied using zidovudine (AZT), as standard compound. The appli cability of two different techniques to separate unbound drug from drug-pro tein complex was analyzed: the gel filtration and ultrafiltration methods. Ultrafiltration was found to be an adequate procedure for the separation of unbounded drug from the drug-protein complex. Incubation temperature rangi ng from 0 to 37 degreesC did not modify considerably the bound fractions. T he same effects were observed as HSA concentration was modified. Binding as says of studied compounds to purified 1% (w/v) HSA at 0 degreesC, indicate that bound fraction of 2-7 ranges from 13 to 47%, exhibiting a higher affin ity to HSA than AZT (12%), which would introduce some interesting improveme nts in their pharmacokinetic properties. In addition, by means of displacem ent studies using HSA site specific drugs such as diazepam and salicylate, it was determined that AZT binds to site I of the HSA molecule, by a mainly entropy driven process (DeltaS = 10.834 cal/mol degreesK), being these obs ervations extensive to 2-7. Some structural basis to explain enhanced affin ity of these novel derivatives was also established. (C) 2001 Academic Pres s.