Vol. 282, Issue 3, 1572-1580, 1997

Interactions with Human Blood in Vitro and Pharmacokinetic Properties in Mice of Liposomal N⁴-Octadecyl-1--D-arabinofuranosylcytosine, A New Anticancer Drug¹

Sibylle K. M. Koller-Lucae, Herbert Schott and Reto A. Schwendener

Division of Cancer Research, Department of Pathology, University Hospital, Zürich, Switzerland (S.K.M.K.-L., R.A.S.) and Institute of Organic Chemistry, University of Tübingen, Germany (H.S.)

The interactions of N⁴-octadecyl-1--D-arabinofuranosylcytosine (NOAC), a lipophilic derivative of 1--D-arabinofuranosylcytosine (ara-C), were studied in vitro with human blood components. Binding of NOAC incorporated into liposomes to erythrocytes (Ec) was saturated at 63 nmol/10⁹ Ec and binding analysis resulted in a weak affinity of 3 × 10³ liters/mol and 4 × 10⁷ binding sites per Ec. The Ec partition coefficient D_Ec was approximately 4, which demonstrates the high accumulation of NOAC in Ec membranes. The calculated fraction f_b of drug 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 lipoproteins (LDL) at 36%, to high-density lipoproteins at 21%, to albumin and other proteins at 12% and to very-low-density lipoproteins at 5%. Comparable results were obtained for the analog N⁴-hexadecyl-1--D-arabinofuranosylcytosine and when the drugs were dissolved in dimethyl sulfoxide. The biodistribution of liposomal NOAC in ICR mice after intravenous application revealed a biphasic blood concentration versus time curve with a distribution half-life t_1/2 of 23 min and an elimination half-life t_1/2 of 7 h. The drug was distributed mainly into the liver with an organ load of 69% and with an elimination half-life of 8 h. The strong affinity of NOAC to LDL might be exploited for the enhanced uptake of the drug in tumor cells expressing high numbers of LDL receptor molecules.