Binding of Fluvastatin to Blood Cells and Plasma Proteins

The binding of fluvastatin, an inhibitor of hydroxymethylglutaryl coenzyme A reductase, to plasma proteins and red blood cells of rat, dog, and human in vitro was determined by ultrafiltration. Additionally, the stereospecificity of fluvastatin binding to proteins and the potential interaction between fluvastatin and the highly protein bound drugs warfarin, salicylic acid, and gfyburide were investigated. Only a small fraction of fluvastatin in blood was taken up by the blood cells, amounting to 19–33% in the rat and ≤ 15% in dog and humans. The plasma:blood fluvastatin ratio in these species at 37°C was ≥1.4. In human blood, this ratio was temperature independent, in the plasma concentration range 25–50 000 ng/mC fluvastatin was ≥98% bound to proteins. The binding was concentration dependent in the rat, but not In the dog and human. Both enantiomers of fluvastatin were >99% bound in normal human plasma, the binding of each being unaffected by the presence of the other. A major fluvastatin-binding protein in human plasma was albumin, whereas binding to α1-acid glycoprotein was relatively weak and concentration dependent. At therapeutic concentrations in normal human plasma, the protein binding of fluvastatin (0.1 μg/mL) was unaffected by warfarin (1–10 μg/mL), salicylic acid (50-150 μ/mL), and glyburide (0.1–1 μ/mL). Similarly, fluvastatin had no influence on the binding of these compounds. In diluted human albumin solution (29 μM), bound fluvastatin was displaced by all three co-solutes tested. The total binding constant of fluvastatin was reduced by ˜40%, 50%, and sevenfold in the presence of warfarin, glyburide, and salicylic add, respectively. Conversely, fluvastatin reduced the total binding constant of salicylic add by ˜34% but had little effect on the binding of warfarin and glyburide. The mutual inhibition between fluvastatin and salicylic add appears to be of the competitive type.