کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
5521524 1545306 2017 13 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Role of regional absorption and gastrointestinal motility on variability in oral absorption of a model drug
ترجمه فارسی عنوان
نقش جذب منطقه ای و تحرک دستگاه گوارش بر تغییرات در جذب دهانی یک دارو مدل
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی بیوتکنولوژی یا زیست‌فناوری
چکیده انگلیسی

Variability in oral absorption in pre-clinical species makes human dose projection challenging. In this study, we investigated the mechanistic basis of variability in oral absorption of a model hydrophobic compound with pH-dependent solubility, BMS-955829, after oral dosing in rats, dogs, and cynomolgus monkeys. The contribution of regional absorption to pharmacokinetic variability was assessed in ported monkeys by direct intraduodenal and intraileal administration. The effect of BMS-955829 on gastric emptying and intestinal motility was investigated by radiography after co-administration of barium. BMS-955829 exhibited species dependent oral bioavailability, with high variability in monkeys. During regional absorption studies, highest rate of drug absorption was observed after direct intraduodenal administration. Radiography studies indicated that BMS-955829 slowed gastric emptying and intestinal motility. The effect of rate and site of drug release on oral exposure was studied using different drug product formulations. Reducing the rate of drug release reduced oral exposure variability without compromising exposure in cynomolgus monkeys. This effect was likely mediated by avoidance of rapid initial absorption and drug effect on gastric emptying and intestinal transit within the biorelevant timeframe. Thus, drug release rate can modulate the effect of physiological factors on variability in the oral absorption of sensitive compounds.

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ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: European Journal of Pharmaceutics and Biopharmaceutics - Volume 117, August 2017, Pages 333-345
نویسندگان
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