| Abstract
| - The extravascular diffusion of antitumor agents is a key determinant of their therapeuticactivity, but the relationships between physicochemical properties of drugs and their extravascular transport are poorly understood. It is well-known that drug lipophilicity plays animportant role in transport across biological membranes, but the net effect of lipophilicity ontransport through multiple layers of tumor cells is less clear. This study examines the influenceof lipophilicity (measured as the octanol−water partition coefficient P) on the extravasculartransport properties of the hypoxic cytotoxin tirapazamine (TPZ, 1) and a series of 13 neutralanalogues, using multicellular layers (MCLs) of HT29 human colon carcinoma cells as an invitro model for the extravascular compartment of tumors. Flux of drugs across MCLs wasdetermined using diffusion chambers, with the concentration−time profile on both sides of theMCL measured by HPLC. Diffusion coefficients in the MCLs (DMCL) were inversely proportionalto Mr0.5 (Mr, relative molecular weight), although this was a minor contributor to differencesbetween compounds over the narrow Mr range investigated. Differences in lipophilicity had alarger effect, with a sigmoidal dependence of DMCL on logP. Correcting for Mr differences,lipophilic compounds (logP> 1.5) had ca. 15-fold higher DMCL than hydrophilic compounds(log P< −1). Using a pharmacokinetic/pharmacodynamic (PK/PD) model in which diffusion inthe extravascular compartment of tumors is considered explicitly, we demonstrated that hypoxiccell kill is very sensitive to changes in extravascular diffusion coefficient of TPZ analogueswithin this range. This study shows that simple monosubstitution of TPZ can alter log P enoughto markedly improve extravascular transport and activity against target cells, especially ifrates of metabolic activation are also optimized.
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