Pharmacokinetic modeling of ascorbate diffusion through normal and tumor tissue

• Published in: Free radical biology & medicine Vol. 77; pp. 340 - 352
• Main Authors: Kuiper, Caroline, Vissers, Margreet C.M., Hicks, Kevin O.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2014
• Subjects: 2-Oxoglutarate-dependent dioxygenases; Ascorbate; Ascorbic Acid - metabolism; Biological Transport; Coenzymes - metabolism; Diffusion; Free radicals; HT29 Cells; Humans; Hypoxia-inducible factor-1; Kinetics; Mannitol - metabolism; Models, Biological; Pharmacokinetics; Tissue Distribution; Tumor hypoxia; Urea - metabolism; HIF-1; 3D; 2-OGDD; SVCT; Free radicals; MCL; Tumor hypoxia; Ascorbate; Pharmacokinetics; 2-Oxoglutarate-dependent dioxygenases; Hypoxia-inducible factor-1
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2014.09.023

Ascorbate is delivered to cells via the vasculature, but its ability to penetrate into tissues remote from blood vessels is unknown. This is particularly relevant to solid tumors, which often contain regions with dysfunctional vasculature, with impaired oxygen and nutrient delivery, resulting in upregulation of the hypoxic response and also the likely depletion of essential plasma-derived biomolecules, such as ascorbate. In this study, we have utilized a well-established multicell-layered, three-dimensional pharmacokinetic model to measure ascorbate diffusion and transport parameters through dense tissue in vitro. Ascorbate was found to penetrate the tissue at a slightly lower rate than mannitol and to travel via the paracellular route. Uptake parameters into the cells were also determined. These data were fitted to the diffusion model, and simulations of ascorbate pharmacokinetics in normal tissue and in hypoxic tumor tissue were performed with varying input concentrations, ranging from normal dietary plasma levels (10–100μM) to pharmacological levels (>1mM) as seen with intravenous infusion. The data and simulations demonstrate heterogeneous distribution of ascorbate in tumor tissue at physiological blood levels and provide insight into the range of plasma ascorbate concentrations and exposure times needed to saturate all regions of a tumor. The predictions suggest that supraphysiological plasma ascorbate concentrations (>100μM) are required to achieve effective delivery of ascorbate to poorly vascularized tumor tissue. [Display omitted] •The diffusion of ascorbate through normal and tumor tissue was modeled in vitro.•Ascorbate diffused slowly and delivery from the vasculature was similar to that of oxygen.•Cellular ascorbate levels were predicted to be acutely dependent on plasma supply.•Poorly vascularized tumor tissue could have compromised ascorbate delivery.•Supraphysiological ascorbate levels may overcome the diffusion barrier in tumors.