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The protein-binding characteristics of the angiotensin II receptor antagonist valsartan were determined in vitro by equilibrium dialysis, using 14C-labeled valsartan with serum from healthy donors, plasma from patients who had received valsartan, serum or plasma from animals, and purified human plasma proteins. The binding of valsartan was high (96 +/- 2%) in human serum at concentrations ranging from 0.05 micrograms/mL to 5 micrograms/mL. A comparable extent of binding (85-99%) was recorded in plasma from patients after repeated administration of valsartan. Albumin (binding 92%) is the main protein involved in the binding to plasma proteins, while the binding to alpha 1-acid glycoprotein was low (22%) and to gamma globulins, negligible. Although highly bound, valsartan was not displaced in vitro by hydrochlorothiazide, diclofenac, furosemide, and warfarin. A high extent of binding was found in rat, dog, and rabbit serum and in marmoset plasma, while a lower binding was found in mouse serum.

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%).

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