Summary
l4C-0-[3-(4-<2-methoxyphenyl>-l-piperazinyl)-2-hydroxypropyl]-3-methoxybenzaldoxim dihydrochloride (HWA 923) was well absorbed (≃80%) in rat and dog. In normal animals 37-48% of the radioactivity from a 2 mg/kg of body weight oral or parenteral dose was excreted in the urine, and 48–50% in the faeces. When14C-HWA 923 was given orally to rats with biliary cannulae, only ≃10% of the dose was excreted in the urine and ≃ 68% appeared in the bile. If bile, collected from animals given l4C-HWA 923, was re-infused intraduodenally into surgically prepared rats,≃ 12% was re-excreted in the urine, and ≃ 55% re-excreted in the bile.
There were considerably higher levels of radioactivity present in rat blood following intravenous administration ofl4C-HWA 923 than after an oral dose, suggesting that radioactivity given via the oral routemight be excreted directly into the bile without reaching the systemic circulation. In dog, a significant “first-pass” effect was seen for HWA 923.
In a surgically prepared dog, where the bile collection was intermittent, 32% of the dose was excreted in the urine and 46% in the bile. An estimated 73% of the dose would have been present in bile, if continuous collection had taken place.
In rat, the major urinary metabolite (up to 40% of the urinary radioactivity) was identified, after specific hydrolysis with β-glucuronidase, as a demethylated product of HWA 923 by co-chromatography in four solvent systems. This metabolite was present, in rat bile as the conjugates (≃40% of the biliary radioactivity), together with significant quantities ≃20%) of conjugated HWA 923. The two products were also found on hydrolysis of bile, using gut microflora. Similar results were obtained from dog samples.
It is postulated that hydrolysis of the glucuronides of unchanged HWA 923 and its demethylated metabolite by gut micro flora results in enterohepatic circulation of these two compounds in rat and dog.
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An erratum to this article is available at http://dx.doi.org/10.1007/BF03188734.
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Paul, H., Illing, A. & House, E.S.A. Enterohepatic circulation in rat and dog of14C-0-[3-(4-<2-methoxyphenyl>-1 -piperazinyl)-2-hydroxypropyl]-3-methoxy-benzaldoxim dihydrochloride and it’s demethylated metabolite. European Journal of Drug Metabolism and Pharmacokinetics 6, 303–312 (1981). https://doi.org/10.1007/BF03189530
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DOI: https://doi.org/10.1007/BF03189530