Interaction of N-alkylanthracyclines with lipid bilayers: correlations between partition coefficients, lipid phase distributions and thermotropic behavior.
The thermotropic behavior of multilamellar vesicles of dipalmitoylphosphatidylcholine (DPPC), or of DPPC in admixture with cardiolipin or cholesterol, in the presence of various N-alkyl derivatives of both adriamycin and adriamycin-14-valerate has been investigated by high sensitivity differential scanning calorimetry. The analogues, particularly the 14-valerate derivatives, which were most lipophilic as judged by their lipid/buffer, and to a lesser extent by their octanol/buffer, partition coefficients, were the most effective in depressing the tm of the investigated lipids; correlations, however, were not absolute. Other factors, such as the distribution of the drugs between the solid and liquid-crystalline phases of the bilayer, were also important to the observed membrane perturbations. With all anthracyclines, however, no major changes in the transition enthalpy were observed. In the case of vesicles prepared from pure DPPC, curve fitting analysis based on ideal solution theory (J.M. Sturtevant (1984) Proc. Natl. Acad. Sci. USA 81, 1398-1400) applied at relatively low drug concentrations where single peak transitions were produced, adequately described the differential scanning calorimetric results. At high drug concentrations, however, the presence of multi-peak transitions were indicative of non-ideality.
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Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510.
Ghosaini
L
L
Inouchi
N
N
Kitamura
S
S
Seshadri
R
R
Israel
M
M
Sartorelli
A C
AC
Sturtevant
J M
JM
D015060:1,2-Dipalmitoylphosphatidylcholine; D020003:1-Octanol; D000478:Alkylation; D002021:Buffers; D002152:Calorimetry, Differential Scanning; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000378:metabolism; D008051:Lipid Bilayers / Q000378:metabolism*; D008956:Models, Chemical; D000442:Octanols; D012995:Solubility; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D002021:Buffers; D008051:Lipid Bilayers; D000442:Octanols; D015060:1,2-Dipalmitoylphosphatidylcholine; D004317:Doxorubicin; D020003:1-Octanol