Abstract
The interactions of N4-octadecyl-1-β-d-arabinofuranosylcytosine (NOAC), a lipophilic derivative of 1-β-d-arabinofuranosylcytosine (ara-C), were studiedin 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 coefficientD Ec was approximately 4, which demonstrates the high accumulation of NOAC in Ec membranes. The calculated fractionf 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-β-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 versustime curve with a distribution half-life t 1/2αof 23 min and an elimination half-life t 1/2βof 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.
Footnotes
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Send reprint requests to: Reto A. Schwendener, Ph.D., Department of Pathology, Division of Cancer Research, University Hospital, Schmelzbergstrasse 12, CH-8091 Zürich, Switzerland.
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↵1 This work was supported by a grant from the E.G., G., G., and Ch. Sassella Foundation (to S.K.M.K.-L.) and in part by a grant from the Stiftung für angewandte Krebsforschung (to R.A.S.).
- Abbreviations:
- ara-C
- 1-β-d-Arabinofuranosylcytosine
- ara-U
- 1-β-d-arabinofuranosyluracil
- NOAC
- N4-octadecyl-1-β-d-arabinofuranosylcytosine
- NHAC
- N4-hexadecyl-1-β-d-arabinofuranosylcytosine
- SPC
- soy phosphatidylcholine
- PB
- phosphate buffer
- saline/EDTA
- saline containing 0.01% EDTA
- DMSO
- dimethyl sulfoxyde
- EDTA
- ethylenediaminetetraacetic acid
- Ec
- erythrocytes
- Bmax
- maximal drug binding capacity
- Kd
- ligand concentration at half-maximal binding
- r
- binding rate
- cu
- unbound drug
- AEc
- drug bound to Ec
- Ectot
- total concentration of Ec
- DEc
- Ec partition coefficient
- Ablood
- total drug in whole blood
- Aplasma
- drug in the plasma fraction
- H
- hematocrit
- fb
- plasma protein-binding fraction
- HDL
- high-density lipoprotein
- LDL
- low-density lipoprotein
- VLDL
- very-low-density lipoprotein
- KBr
- potassium bromide
- t1/2α
- distribution half-life
- t1/2β
- elimination half-life
- Vd(area)
- area-derived apparent volume of distribution
- Vc
- apparent volume of the central compartment
- Vp
- apparent volume of the peripheral compartment
- Cltotal
- systemic clearance
- AUC(tr. 0→∞)
- area under the curve for time zero to infinity calculated model-independently with the trapezoidal rule
- AUMC
- area under the moment curve
- cblood
- drug concentration in blood
- cplasma
- drug concentration in plasma
- Vblood
- total blood volume
- MRT
- mean residence time
- Clin
- tissue uptake rate index
- T(t1)
- amount of drug in the tissue at time t 1
- Clorgan
- organ clearance
- Worgan
- organ weight
- HPLC
- high-performance liquid chromatography
- Received November 11, 1996.
- Accepted May 14, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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