کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
5860742 1133236 2011 9 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Development and application of a physiologically based pharmacokinetic model for triadimefon and its metabolite triadimenol in rats and humans
موضوعات مرتبط
علوم زیستی و بیوفناوری علوم محیط زیست بهداشت، سم شناسی و جهش زایی
پیش نمایش صفحه اول مقاله
Development and application of a physiologically based pharmacokinetic model for triadimefon and its metabolite triadimenol in rats and humans
چکیده انگلیسی

A physiologically based pharmacokinetic (PBPK) model was developed for the conazole fungicide triadimefon and its primary metabolite, triadimenol. Rat tissue:blood partition coefficients and metabolic constants were measured in vitro for both compounds. Pharmacokinetic data for parent and metabolite were collected from several tissues after intravenous administration of triadimefon to male Sprague-Dawley rats. The model adequately simulated peak blood and tissue concentrations but predicted more rapid clearance of both triadimefon and triadimenol from blood and tissues. Reverse metabolism of triadimenol to triadimefon in the liver was explored as a possible explanation of this slow clearance, with significant improvement in model prediction. The amended model was extrapolated to humans using in vitro metabolic constants measured in human hepatic microsomes. Human equivalent doses (HEDs) were calculated for a rat no observable adverse effect level (NOAEL) dose of 3.4 mg/kg/day using area under the concentration curve (AUC) in brain and blood for triadimefon and triadimenol as dosimetrics. All dosimetric-based HEDs were 25-30 fold above the human oral reference dose of 0.03 mg triadimefon/kg/day, but did not account for intra-human variability or pharmacodynamic differences. Ultimately, derivations of this model will be able to better predict the exposure profile of these and other conazole fungicides in humans.

► A PBPK model was developed for triadimefon and triadimenol in rodents and humans. ► Pharmacokinetics after IV exposure were measured for both chemicals in rats. ► Reversible metabolism and binding were explored as drivers of pharmacokinetics. ► Extrapolation to humans indicates regulatory exposure limits may be high. ► The model reveals significant data gaps but illuminates a path to address them.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Toxicology Letters - Volume 205, Issue 2, 28 August 2011, Pages 154-162
نویسندگان
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