BINDING OF DRUGS TO HUMAN PLASMA-PROTEINS, EXEMPLIFIED BY SN(IV)-ETIOPURPURIN DICHLORIDE DELIVERED IN CREMOPHOR AND DMSO

1. The mode-delivery-effect upon the binding of Sn(IV)-etiopurpurin di chloride (SnET2) in human plasma has been studied by ultracentrifugati on, combined with absorption and fluorescence spectroscopy. SnET2 was delivered to plasma either in Cremophore EL (CRM) or in dimethyl sulfo xide (DMSO). To facilitate interpretation, optical, conductivity and a ggregation properties of SnET2 were obtained for various solutions. 2. The second order rate constant for the aggregation of SnET2 monomers seemed to be remarkably small, of the order of 10(3) M-1 min-1. 3. SnE T2 was bound as monomeric entities. Such entities had environmental-se nsitive fluorescent properties dependent on the type of protein or sol vent (DMSO, CRM, H2O) with which they interacted. 4. SnET2 showed satu rable binding with high density subfraction(s) of high density lipopro teins and with one or more high density proteins Complete or substanti al saturation was achieved at the SnET2 level of 3.5 mug/ml. Such bind ing might be mediated by apolipoprotein D and alpha1-acid glycoprotein . 5. There was little effect of SnET2 concentrations (3.5-35 mug SnET2 /ml) upon the plasma binding of SnET2, irrespective of the mode of del ivery. 6. The percentages of SnET2 bound to low density lipoproteins ( LDL), high density lipoproteins (HDL), and high density proteins (HDP) were 10, 70 and 20%, respectively, for delivery in DMSO. The value fo r LDL also includes binding with very low density lipoproteins (VLDL). For delivery in CRM the corresponding values were 20, 50 and 30%. App arently, CRM interacted with HDL entities and reduced their affinity f or SnET2. 7. The distribution pattern of SnET2 among lipoproteins refl ects interactions with apoproteins and/or with surface phospholipids r ather than with core lipid constituents of lipoproteins. 8. Conductivi ty measurements showed that SnET2 was partly an ionic entity in water. 9. The plasma binding of SnET2 is compared with the corresponding bin ding of other drugs, both tetrapyrroles and nontetrapyrroles.