Plasma protein binding of letrozole, a new nonsteroidal aromatase enzyme inhibitor.
The protein binding characteristics of the nonsteroidal aromatase inhibitor letrozole were determined using 14C-labeled letrozole. The binding of letrozole in human serum was 60.1 +/- 2.9% as a mean obtained in six individual sera and was similar in human plasma. The binding in human serum remained constant at concentrations of letrozole ranging from 10 to 500 ng/mL. A similar binding value in human serum was obtained using equilibrium dialysis and ultrafiltration technique. Albumin (binding 55.1 +/- 1.4%) is the main protein involved in the drug binding to plasma proteins. Increases in letrozole concentration (10-500 ng/mL) had no effect on binding. Albumin binding appeared to be nonsaturable with a binding capacity of 2 L/mmol. Binding to alpha1-acid glycoprotein and to gamma globulins was lower than 10%. The fraction in erythrocytes with a hematocrit of 0.4 was found to be 35.2 +/- 2.7%. Letrozole binding to serum proteins of rat, dog, mouse, and rabbit was approximately 10% lower than that in human serum and approximately 20% lower than that in baboons. Tamoxifen (100-1,500 ng/mL) had no effect on the in vitro binding of letrozole. Ex vivo binding in plasma from patients after repeated administration of letrozole alone (61.4 +/- 2.6%) was the same as after combined administration of letrozole and tamoxifen (60.0 +/- 3.2%).
Colussi
D M
DM
Department of Drug Metabolism and Pharmacokinetics, Novartis Pharma S.A., Rueil-Malmaison, France.
Parisot
C Y
CY
Lefèvre
G Y
GY
D000818:Animals; D047072:Aromatase Inhibitors; D001798:Blood Proteins / Q000378:metabolism; D003956:Dialysis; D004285:Dogs; D004791:Enzyme Inhibitors / Q000097:blood*; D004912:Erythrocytes / Q000378:metabolism; D004965:Estrogen Antagonists / Q000494:pharmacology; D006801:Humans; D007202:Indicators and Reagents; D000077289:Letrozole; D051379:Mice; D009570:Nitriles / Q000097:blood*; D010949:Plasma / Q000378:metabolism; D011485:Protein Binding; D011817:Rabbits; D051381:Rats; D013629:Tamoxifen / Q000494:pharmacology; D014230:Triazoles / Q000097:blood*; D014462:Ultrafiltration
D047072:Aromatase Inhibitors; D001798:Blood Proteins; D004791:Enzyme Inhibitors; D004965:Estrogen Antagonists; D007202:Indicators and Reagents; D009570:Nitriles; D014230:Triazoles; D013629:Tamoxifen; D000077289:Letrozole