Abstract
This study compares the biliary and urinary metabolic profiles of 1,2-diethyl-3-hydroxypyridin-4-one (CP94), an orally active iron chelator, in the normal rat. Surprisingly, CP94 was found to form two phase II metabolites, the 3-O- and 4-O-glucuronides. These glucuronides accounted for 38 and 28% of the administered CP94 dose, in bile and urine, respectively. Unchanged CP94 accounted for 5% of the CP94 dose in both bile and urine. The 2-(1′-hydroxy) metabolite of CP94 was found to be the dominant metabolite in urine. In addition, an unstable metabolite was detected in the bile although its structure remains unknown at the present stage. The excretion of iron in bile, after administration of CP94, was found to parallel the biliary elimination of CP94 together with its hydroxylated derivatives, indicating the importance of metabolites in iron excretion.
Footnotes
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Send reprint requests to: Professor R.C. Hider, Department of Pharmacy, King's College London, Franklin-Wilkins Building, Stamford Street, London SE1 8WA, UK. E-mail:r.hider{at}kcl.ac.uk
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This work was supported by Apotex Research Inc. Canada and European Community Biomedical Grant BMH4-CT97–2149.
- Abbreviations used are::
- HPOs
- 3-hydroxypyridin-4-ones
- CP94
- 1,2-diethyl-3-hydroxypyridin-4-one
- CP102
- 1-(2′-hydroxyethyl)-2-ethyl-3-hydroxypyridin-4-one
- CP365
- 1-ethyl-2-(1′-hydroxyethyl)-3-hydroxypyridin-4-one
- UDPGA
- 5′-diphosphoglucuronic acid
- LC-MS
- liquid chromatography-mass spectrometry
- MOPS
- 3-[N-morpholino]propanesulfonic acid
- Received December 27, 1999.
- Accepted April 17, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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