INTERACTIONS WITH HUMAN BLOOD IN-VITRO AND PHARMACOKINETIC PROPERTIESIN MICE OF LIPOSOMAL N-4-OCTADECYL-1-BETA-D-ARABINOFURANOSYLCYTOSINE,A NEW ANTICANCER DRUG

The interactions of N-4-octadecyl-1-beta-D-arabinofuranosylcytosine (N OAC), a lipophilic derivative of 1-beta-D-arabinofuranosylcytosine (ar a-C), were studied in vitro with human blood components. Binding of NO AC incorporated into liposomes to erythrocytes (Ec) was saturated at 6 3 nmol/10(9) Ec and binding analysis resulted in a weak affinity of 3 x 10(3) liters/mol and 4 x 10(7) binding sites per Ec. The Ec partitio n coefficient D-Ec was approximately 4, which demonstrates the high ac cumulation of NOAC in Ec membranes. The calculated fraction f(b) of dr ug bound to plasma proteins was 30%. Analysis of serum protein binding of NOAC was done by density gradient ultracentrifugation and agarose gel electrophoresis. Liposomal NOAC was distributed to low-density lip oproteins (LDL) at 36%, to high-density lipoproteins at 21%, to albumi n and other proteins at 12% and to very-low-density lipoproteins at 5% . Comparable results were obtained for the analog N-4-hexadecyl-1-beta -D-arabinofuranosylcytosine and when the drugs were dissolved in dimet hyl sulfoxide. The biodistribution of liposomal NOAC in ICR mice after intravenous application revealed a biphasic blood concentration versu s time curve with a distribution half-life t(1/2 alpha) of 23 min and an elimination half-life t(1/2 beta) of 7 h. The drug was distributed mainly into the liver with an organ load of 69% acid with an eliminati on half-life of 8 h. The strong affinity of NOAC to LDL might be explo ited for the enhanced uptake of the drug in tumor cells expressing hig h numbers of LDL receptor molecules.