IN-VITRO PROTEIN-BINDING CHARACTERISTICS OF ATEVIRDINE AND ITS N-DEALKYLATED METABOLITE

The in vitro protein-binding characteristics of atevirdine (ATV), a no n-nucleoside reverse transcriptase inhibitor with activity against HIV -1, and its N-dealkylated metabolite (N-ATV) were studied using equili brium dialysis. ATV and N-ATV were studied at concentrations of 5, 10, 20, and 30 mu M in five protein-containing solutions [albumin 4%, pla sma, serum, immune globulin (IgG) 1.5%, alpha(1)-acid glycoprotein (AA G)] for 5 h at 37 degrees C. All samples were analyzed by high-perform ance liquid chromatography. The free fraction of atevirdine in plasma, albumin, and serum was 0.01-0.02 over the range of drug concentration s studied. The fraction unbound (f(u)) in these protein solutions stat istically differed from IgG and AAG (P < 0.05), where the fraction unb ound averaged 0.96 and 0.53, respectively. N-ATV had a similar binding profile as ATV with a fraction unbound of 0.04, 0.03, 0.03 in albumin , plasma and serum, respectively. A difference existed in N-ATV bindin g when compared to IgG and AAG with an average f(u) of 0.87 and 0.59 ( P < 0.05 vs. plasma). The potential clinical implications of the high degree of protein binding for ATV and N-ATV are discussed.