In vitro protein-binding characteristics of atevirdine and its N-dealkylated metabolite

The in vitro protein-binding characteristics of atevirdine (ATV), a non-nucleoside reverse transcriptase inhibitor with activity against HIV-1, and its N-dealkylated metabolite (N-ATV) were studied using equilibrium dialysis. ATV and N-ATV were studied at concentrations of 5, 10, 20, and 30 μM in five protein-containing solutions [albumin 4%, plasma, serum, immune globulin (IgG) 1.5%, α₁-acid glycoprotein (AAG)] for 5 h at 37°C. All samples were analyzed by high-performance liquid chromatography. The free fraction of atevirdine in plasma, albumin, and serum was 0.01-0.02 over the range of drug concentrations studied. The fraction unbound (f_u) in these protein solutions statistically differed from IgG and AAG (P < 0.05), where the fraction unbound 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 binding 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.