| Autor: |
Pruijn, F. B., Sturman, J. R., Liyanage, H. D. S., Hicks, K. O., Hay, M. P., Wilson, W. R. |
| Zdroj: |
Journal of Medicinal Chemistry; February 2005, Vol. 48 Issue: 4 p1079-1087, 9p |
| Abstrakt: |
The extravascular diffusion of antitumor agents is a key determinant of their therapeutic activity, but the relationships between physicochemical properties of drugs and their extravascular transport are poorly understood. It is well-known that drug lipophilicity plays an important role in transport across biological membranes, but the net effect of lipophilicity on transport through multiple layers of tumor cells is less clear. This study examines the influence of lipophilicity (measured as the octanol−water partition coefficient P) on the extravascular transport properties of the hypoxic cytotoxin tirapazamine (TPZ, 1) and a series of 13 neutral analogues, using multicellular layers (MCLs) of HT29 human colon carcinoma cells as an in vitro model for the extravascular compartment of tumors. Flux of drugs across MCLs was determined using diffusion chambers, with the concentration−time profile on both sides of the MCL measured by HPLC. Diffusion coefficients in the MCLs (DMCL) were inversely proportional to Mr0.5 (Mr, relative molecular weight), although this was a minor contributor to differences between compounds over the narrow Mr range investigated. Differences in lipophilicity had a larger effect, with a sigmoidal dependence of DMCL on log P. Correcting for Mr differences, lipophilic compounds (log P > 1.5) had ca. 15-fold higher DMCL than hydrophilic compounds (log P < −1). Using a pharmacokinetic/pharmacodynamic (PK/PD) model in which diffusion in the extravascular compartment of tumors is considered explicitly, we demonstrated that hypoxic cell kill is very sensitive to changes in extravascular diffusion coefficient of TPZ analogues within this range. This study shows that simple monosubstitution of TPZ can alter log P enough to markedly improve extravascular transport and activity against target cells, especially if rates of metabolic activation are also optimized. |
| Databáze: |
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