title: Pharmacokinetic modeling of ascorbate diffusion through normal and tumor tissue.
abstract: 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 (10-100 μM) to pharmacological levels (>1 mM) 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 (>100 μM) are required to achieve effective delivery of ascorbate to poorly vascularized tumor tissue.
authors.affiliation: Centre for Free Radical Research, Pathology Department, University of Otago at Christchurch, Christchurch, New Zealand. Electronic address: caroline.kuiper@well.ox.ac.uk.
authors.forename: Caroline
authors.initials: C
authors.lastname: Kuiper
authors.affiliation: Centre for Free Radical Research, Pathology Department, University of Otago at Christchurch, Christchurch, New Zealand.
authors.forename: Margreet C M
authors.initials: MC
authors.lastname: Vissers
authors.affiliation: Auckland Cancer Society Research Centre, University of Auckland, Auckland, New Zealand.
authors.forename: Kevin O
authors.initials: KO
authors.lastname: Hicks
mesh_terms: D001205:Ascorbic Acid / Q000378:metabolism*; D001692:Biological Transport; D003067:Coenzymes / Q000378:metabolism; D004058:Diffusion; D019073:HT29 Cells; D006801:Humans; D007700:Kinetics; D008353:Mannitol / Q000378:metabolism; D008954:Models, Biological; D014018:Tissue Distribution; D014508:Urea / Q000378:metabolism
chemical_list: D003067:Coenzymes; D008353:Mannitol; D014508:Urea; D001205:Ascorbic Acid
keywords: 2-Oxoglutarate-dependent dioxygenases; Ascorbate; Free radicals; Hypoxia-inducible factor-1; Pharmacokinetics; Tumor hypoxia