Header

UZH-Logo

Maintenance Infos

Interactions with human blood in vitro and pharmacokinetic properties in mice of liposomal N4-octadecyl-1-beta-D-arabinofuranosylcytosine, a new anticancer drug


Koller-Lucae, S K; Schott, H; Schwendener, R (1997). Interactions with human blood in vitro and pharmacokinetic properties in mice of liposomal N4-octadecyl-1-beta-D-arabinofuranosylcytosine, a new anticancer drug. Journal of Pharmacology and Experimental Therapeutics, 282(3):1572-1580.

Abstract

The interactions of N4-octadecyl-1-beta-D-arabinofuranosylcytosine (NOAC), a lipophilic derivative of 1-beta-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/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 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-beta-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 t1/2alpha of 23 min and an elimination half-life t1/2beta 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.

Abstract

The interactions of N4-octadecyl-1-beta-D-arabinofuranosylcytosine (NOAC), a lipophilic derivative of 1-beta-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/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 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-beta-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 t1/2alpha of 23 min and an elimination half-life t1/2beta 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.

Statistics

Citations

19 citations in Web of Science®
19 citations in Scopus®
Google Scholar™

Altmetrics

Downloads

99 downloads since deposited on 20 Oct 2009
9 downloads since 12 months
Detailed statistics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Molecular Cancer Research
07 Faculty of Science > Institute of Molecular Cancer Research
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:1997
Deposited On:20 Oct 2009 14:33
Last Modified:06 Dec 2017 21:25
Publisher:American Society for Pharmacology and Experimental Therapeutics
ISSN:0022-3565
Additional Information:Free full text article
PubMed ID:9316874

Download

Download PDF  'Interactions with human blood in vitro and pharmacokinetic properties in mice of liposomal N4-octadecyl-1-beta-D-arabinofuranosylcytosine, a new anticancer drug'.
Preview
Filetype: PDF
Size: 422kB