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 dichloride (SnET2) in human plasma has been studied by ultracentrifugation, combined with absorption and fluorescence spectroscopy. SnET2 was delivered to plasma either in Cremophore EL (CRM) or in dimethyl sulfoxide (DMSO). To facilitate interpretation, optical, conductivity and aggregation 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. SnET2 was bound as monomeric entities. Such entities had environmental-sensitive fluorescent properties dependent on the type of protein or solvent (DMSO, CRM, H2O) with which they interacted. 4. SnET2 showed saturable binding with high density subfraction(s) of high density lipoproteins and with one or more high density proteins. Complete or substantial saturation was achieved at the SnET2 level of 3.5 micrograms/ml. Such binding might be mediated by apolipoprotein D and alpha 1-acid glycoprotein. 5. There was little effect of SnET2 concentrations (3.5-35 micrograms SnET2/ml) upon the plasma binding of SnET2, irrespective of the mode of delivery. 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 for LDL also includes binding with very low density lipoproteins (VLDL). For delivery in CRM the corresponding values were 20, 50 and 30%. Apparently, CRM interacted with HDL entities and reduced their affinity for SnET2. 7. The distribution pattern of SnET2 among lipoproteins reflects interactions with apoproteins and/or with surface phospholipids rather than with core lipid constituents of lipoproteins. 8. Conductivity measurements showed that SnET2 was partly an ionic entity in water. 9. The plasma binding of SnET2 is compared with the corresponding binding of other drugs, both tetrapyrroles and nontetrapyrroles.
Kongshaug
M
M
Department of Biophysics, Norwegian Radium Hospital, Oslo.
Moan
J
J
Cheng
L S
LS
Garbo
G M
GM
Kolboe
S
S
Morgan
A R
AR
Rimington
C
C
D000327:Adsorption; D001798:Blood Proteins / Q000378:metabolism*; D004121:Dimethyl Sulfoxide; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000378:metabolism; D014677:Pharmaceutical Vehicles; D011092:Polyethylene Glycols; D011166:Porphyrins / Q000097:blood / Q000378:metabolism; D011485:Protein Binding; D012997:Solvents
D001798:Blood Proteins; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D014677:Pharmaceutical Vehicles; D011166:Porphyrins; D012997:Solvents; C022131:cremophor; D011092:Polyethylene Glycols; C063166:tin etiopurpurin; D004121:Dimethyl Sulfoxide