کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2083927 1545352 2013 8 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
An in vitro–in silico–in vivo approach to predicting the oral pharmacokinetic profile of salts of weak acids: Case example dantrolene
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی بیوتکنولوژی یا زیست‌فناوری
پیش نمایش صفحه اول مقاله
An in vitro–in silico–in vivo approach to predicting the oral pharmacokinetic profile of salts of weak acids: Case example dantrolene
چکیده انگلیسی

The aim of this research was to characterize both the dissolution and precipitation kinetics of a model poorly water soluble drug, dantrolene, from its dissolution data, and to develop a predictive model for its oral pharmacokinetics.Physiologically based pharmacokinetic (PBPK) models were coupled with biorelevant dissolution and precipitation data to predict PK profiles of dantrolene in fasted humans. The paddle method was used to obtain the dissolution profiles of free acid form of dantrolene, dantrolene sodium, and the corresponding commercial product in biorelevant media. The Noyes–Whitney model was used to describe the dissolution kinetics, and a first-order equation was employed for estimating the precipitation kinetics from these dissolution profiles. The PBPK model was set up using STELLA® software.After an initial phase of dissolution, the concentration of dantrolene in FaSSGF and FaSSIF-V2 started to decrease again. From the overall dissolution profiles, the dissolution rate constant based on the Noyes–Whitney theory for dissolution and the first-order precipitation rate constant were calculated. The PK profiles predicted under consideration of the precipitation were close to the observed PK profile. By contrast, when only the dissolution was considered, the absorption rate was overestimated. These results indicate that PBPK modeling with dissolution and precipitation kinetics is useful for the predicting the PK profile after oral administration of dantrolene from the sodium salt and suggests a way forward for predicting PK profiles of other salts of weak acids that are poorly soluble.

The diagram shows how dissolution and precipitation are accounted for in the STELLA® model when dantrolene is administered as the sodium salt. To adequately describe the pharmacokinetics of dantrolene, it was necessary to account for precipitation of the sodium salt in both the stomach and small intestine. For dantrolene, re-dissolution of the precipitate contributes little or nothing to the plasma profile.Figure optionsDownload high-quality image (129 K)Download as PowerPoint slide

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: European Journal of Pharmaceutics and Biopharmaceutics - Volume 84, Issue 1, May 2013, Pages 200–207
نویسندگان
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