In this study the metabolism of the anti-arthritic drug, phenylbutazone, was investigated in female Wistar rats, and the results compared with those of other workers in this field. Two interrelated projects were undertaken. The first covered the pattern of excretion, isolation and characterisation of the metabolites and decomposition products of phenylbutazone in rats dosed post-orally with the drug. It was found that the major route of excretion was via the urine and over 50% of the administered dose was excreted in the first 24 hours by this route. A small percentage of the dose was excreted in the faeces. The following compounds were identified using chromatographic and autoradiographic techniques: p-Hydroxy derivative of phenylbutazone γ-Hydroxy derivative of phenylbutazone in both its molecular forms (ring lactone and straight chain hydroxyl) 4-Hydroxy derivative of phenylbutazone p-γ-Dihydroxy derivative of phenylbutazone p-4-Dihydroxy derivative of phenylbutazone Hydrolysable conjugates (possibly glucuronides) Water soluble non-hydrolysable conjugates. The second project dealt with the quantitation of the water insoluble compounds isolated in the initial work. Using a unique technique, combining inverse isotope dilution assay and spectrophotometric analysis, it was found that the major metabolite was the γ-hydroxy derivative of phenylbutazone, present in both its molecular forms. Oxyphenbutazone was a minor metabolite and the p-γ-dihydroxy derivative of phenylbutazone was present only in very low concentration. These results did not conform with those of previous workers in this field who reported the γ-hydroxy derivative of phenylbutazone, in one molecular form only, as the major metabolite and the dihydroxy derivative as the second metabolite with a higher concentration in the urine than oxyphenbutazone. This disparity could be due to the fact that these workers took no account of the presence of the two molecular forms of the γ-hydroxy derivative of phenylbutazone with their different polarities and different Rf values. The present study showed that the straight chain hydroxyl isomer was probably mistakenly identified as the p-γ-dihydroxy derivative of phenylbutazone. This theory is supported by the fact that the percentage dose recovered by the previous workers of the γ-hydroxy and p-γ-dihydroxy derivatives together equalled the percentage dose recovered in this study of the two molecular forms of the γ-hydroxy derivative. / KMBT_363 / Adobe Acrobat 9.54 Paper Capture Plug-in
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:rhodes/vital:3832 |
| Date | 18 October 2013 |
| Creators | Alexander, Dorothy Mary |
| Publisher | Rhodes University, Faculty of Pharmacy, Pharmacy |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis, Masters, MSc |
| Format | 224 p., pdf |
| Rights | Alexander, Dorothy Mary |
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