Role of lipoproteins in the plasma binding of SDZ PSC 833, a novel multidrug resistance‐reversing cyclosporin

Abstract

The plasma binding of the cyclosporin D analogue SDZ PSC 833 was investigated in vitro. The plasma total binding constant (corresponding to the bound-to-free concentration or binding ratio) was determined at 37 degrees C by the erythrocyte partitioning technique on plasma samples from three healthy volunteers and three cancer patients. Lipoproteins were also removed from plasma samples from three healthy volunteers by a standard ultracentrifugal technique. SDZ PSC 833 plasma binding was 97.8 +/- 1.1% and 97.3 +/- 0.2% in samples from three healthy volunteers and three cancer patients respectively. More than 95% of blood SDZ PSC 833 was distributed in plasma. When the original plasma samples of three individuals were delipidated, SDZ PSC 833 binding was strongly decreased (58% bound to plasma proteins) and when lipoproteins were resuspended in the delipidated plasma samples to produce varying lipoprotein plasma concentrations, the binding increased continuously with the fraction of added lipoproteins. When lipoproteins were resuspended to restore the original lipoprotein plasma content, the % plasma-bound SDZ PSC 833 increased to 98.2%, close to the value observed with the original plasma (98.7%). These results clearly indicate that SDZ PSC 833 plasma binding is mainly determined by lipoproteins and that in blood, most of SDZ PSC 833 is distributed in plasma.