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 microM in five protein-containing solutions [albumin 4%, plasma, serum, immune globulin (IgG) 1.5%, alpha 1-acid glycoprotein (AAG)] for 5 h at 37 degrees 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 (fu) 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 fu 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.
Rosser
L M
LM
Department of Pharmacy Practice, State University of New York at Buffalo 14260, USA.
O'Donnell
A M
AM
Lee
K M
KM
Morse
G D
GD
D000998:Antiviral Agents / Q000097:blood / Q000378:metabolism*; D003640:Dealkylation; D054303:HIV Reverse Transcriptase; D006801:Humans; D010879:Piperazines / Q000097:blood / Q000378:metabolism*; D011485:Protein Binding; D018894:Reverse Transcriptase Inhibitors
D000998:Antiviral Agents; D010879:Piperazines; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; C076632:atevirdine