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Abstract

Phosphocitrate (PC) has previously demonstrated inhibitory potential against
calcium crystallite formation associated with disease states such as urolithiasis,
atherosclerosis and joint crystal deposition. The compound has proven active when
injected intraperitoneally (ip) and intramuscularly. However, when administered
orally, it has limited bioavailability. The present study has investigated synthesis of an
oral PC prodrug and, in conjunction with determining the metabolic fate of the parent
compound, assessed in viva inhibitory activity of the new PC derivative.
Basic pharmacokinetics of PC were determined by a single intravenous (iv)
injection Uugular vein) of radiolabelled PC followed by measurement within 60 min
of the compound in plasma, urine and selected tissues. The plasma concentration-time
profile of the compound followed a two-compartment model, with an elimination
half-life of 30 min. Uptake of the administered dose accounted for less than 0.1 % in
tissues, with 10 % in urine within 1 h. A capillary electrophoretic system was
optimised for PC identification and measurement in urine. Longer-term studies
involving iv (caudal vein) and ip administrations of non-labelled PC indicated total
excretion of compound occurred within 12 hand 24 h, respectively.
A synthetic strategy was developed for generating a methylacyloxy derivative
of PC. The mono-sodium PC salt was reacted with chloromethylacetate under alkali
conditions, with formamide as the solvent. Partial characterisation of the isolated
product indicated that the PC derivative was water soluble, suggesting that it may not
have been fully esterified, although phosphate esterification did occur as indicated by
thin-layer chromatography. As anticipated, the derivative proved unable to prevent in
vitro the transformation of amorphous calcium phosphate to hydroxyapatite.
Orally administered prodrug inhibited chemically-induced subcutaneous
plaques in rats with a similar potency to that of equimolar doses of ip administered
parent compound. Similar urinary excretion patterns of the parent compound were
observed whether PC was given orally as PC prodrug or ip as the parent compound.
Enzymatic studies in vitro demonstrated slow hydrolysis of prodrug to parent
compound in the presence of plasma with a more rapid hydrolysis noted using a rat
liver homogenate.
For the first time, it has been demonstrated that PC exhibits improved
bioavailability when administered as an oral prodrug derivative, thus offering an
alternate route of administration for its future consideration as a therapeutic drug
against calcinosis.

Item Type:	Thesis - PhD
Authors/Creators:	Parry, Nathan Frank Glynn
Keywords:	Calcification, Prodrugs, Phosphorylation
Copyright Holders:	The Author
Copyright Information:	Copyright 2003 the author - The University is continuing to endeavour to trace the copyright owner(s) and in the meantime this item has been reproduced here in good faith. We would be pleased to hear from the copyright owner(s).
Additional Information:	Thesis (Ph.D.)--University of Tasmania, 2003. Includes bibliographical references
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