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Studies on the oral delivery of phosphocitrate


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Cooper, Chris(Christopher Mark) 1992 , 'Studies on the oral delivery of phosphocitrate', Unspecified thesis, University of Tasmania.

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Phosphocitrate is a potent inhibitor of hydroxyapatite formation with
demonstrated efficacy in preventing the progression of calcific pathologies in
animal models. In the present studies, the oral bioavailability of phosphocitrate
was investigated following administration of the compound by gavage in rats.
Using a calcergic model, inhibitory action by phosphocitrate was evaluated.
Accordingly, the formation of small subcutaneous calcific plaques was
chemically induced. Parameters measured included plaque weight, calcium,
and phosphorus content. The oral and intraperitoneal routes of administration
were compared and dose-response relationships established. Phosphocitrate
was found capable of reducing calcific plaque formation when delivered by
either route. However reduced bioavailability was apparent following
administration by gavage revealing the oral route to be approximately 45 times
less effective on a dose-weight basis than the intraperitoneal route.
The possibility that poor absorption from the small intestine was
responsible for the observed differences was explored. Transport studies using
everted sacs and in situ ligated loops confirmed phosphocitrate absorption. The
data revealed concentration-dependance and the absence of in vitro intestinal
transfer at the lowest concentration (1mM) trialled.
Further studies were necessary to evaluate the extent of phosphocitrate
absorption from the small intestine. Experiments with radiolabelled
phosphocitrate and using an in situ perfusion technique with hepatic portal vein
cannulation yielded additional information. The studies provided conclusive
evidence that limited amounts of intact phosphocitrate were being absorbed.
First pass metabolism to citric acid was observed but this metabolism was not
commensurate with the poor rate of absorption. Studies utilising tricarballylate, a known inhibitor of tricarboxylic acid transport in the intestine, indicated that
the disappearance of phosphocitrate from the intestinal lumen was not affected
by the presence of this transport inhibitor. Consideration of this and everted
sac data gave credence to the suggestion that phosphocitrate transport did not
involve an established tricarboxylic acid transporter.
A preliminary investigation was made into the possibility of improving
the oral bioavailability of phosphocitrate with aliphatic ester prodrugs of
phosphocitrate. Initially the approach was to investigate the synthesis and
ultimate benefit of short (ethyl) and medium chain (octyl) esters. The triethyl
ester of phosphocitrate was synthesised and trialled but the isolation and
purification of the trioctyl ester was not possible within the time frame of these
Conclusions reached in this study were that phosphocitrate was
absorbed following oral administration but that the extent of absorption was
limited. Triethyl phosphocitrate was prepared in an attempt to improve the
transport characteristics of phosphocitrate. Plaque calcification was not
reduced following the administration of this ester. The prodnig approach was
discussed as a possible avenue for improving the absorption of phosphocitrate.

Item Type: Thesis - Unspecified
Authors/Creators:Cooper, Chris(Christopher Mark)
Keywords: Phosphocitrate, Calcification, Phosphocitrate
Copyright Holders: The Author
Copyright Information:

Copyright 1992 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:

Includes bibliographical references (leaves 99-118). Thesis (M.Sc.)--University of Tasmania, 1993

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