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Biological and pharmacokinetic studies on the oral iron chelator 1,2 dimethyl-3-hydroxypyrid-4-one

Hileti, Dona; (1995) Biological and pharmacokinetic studies on the oral iron chelator 1,2 dimethyl-3-hydroxypyrid-4-one. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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The iron chelator 1,2 dimethyl-3-hydroxypyrid-4-one (Deferiprone, L1) is currently the most promising orally active alternative to desferrioxamine (DFO) for the treatment of iron overload. The work contained in this thesis consists of a combination of in vivo and in vitro investigations into the pharmacology and toxicity of L1. in vivo experiments were performed in normal and iron-loaded rats. Parenchymal iron overload was achieved using 3,5,5-trimethylhexanoyl ferrocene. In normal rats, radiolabelled L1 (14C-L1) rapidly penetrated most tissues in the body. Upon intravenous administration, concentrations were highest in the liver, intermediate in the kidneys and gastrointestinal tract and lowest in other tissues examined (blood, bone marrow, heart, spleen, lungs, brain, testes, thyroid, thymus, salivary glands, muscle and pancreas). There was more radioactivity in the liver of iron-loaded animals compared to controls. L1 was effective in promoting faecal iron excretion in iron-loaded rats, presumably due to mobilization of hepatocellular iron stores. Pharmacokinetic experiments showed that parenchymal iron overload decreased the systemic exposure and mean residence time and increased the apparent clearance and volume of distribution of the drug. 14c-L1 was rapidly taken up by normal and sickle red blood cells and by the erythroleukaemia cell line K562, reaching equilibrium across the cell membrane within one minute of addition. 14C-L1 accumulated gradually in thalassaemic RBC which have high levels of intracellular iron, presumably due to the formation of the L1-iron(III) complex which is larger and more hydrophilic than L1 and therefore exits cells more slowly. Incubation of cultured rat hepatocytes with 14C-L1 showed saturable intracellular accumulation of radioactivity by an energy-requiring mechanism, which could be due to intracellular metabolism of L1 or to active transport of L1 into those cells. These findings demonstrate that L1 has excellent membrane permeation characteristics enabling it to access easily various cells and tissues. Complexing of L1 with iron decreases the cellular transport of the drug, leading to potential accumulation of L1 in sites of iron overload. The pharmacokinetic, clinical and possible toxicological implications of this are discussed. L1 and DFO were found to induce apoptosis in proliferating activated T-lymphocytes and in the promyelocytic cell line HL60 but not in resting peripheral blood lymphocytes or granulocytes. The cytotoxicity of both chelators to proliferating cells was mediated through intracellular iron depletion and concominant inhibition of proliferation and DNA synthesis. These results suggest that the intracellular chelation of iron in proliferating cells may be an important mechanism of L1 toxicity.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Biological and pharmacokinetic studies on the oral iron chelator 1,2 dimethyl-3-hydroxypyrid-4-one
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Health and environmental sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10104904
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