Academic Journal
Determination of Unbound Partition Coefficient and in Vitro-in Vivo Extrapolation for SLC13A Transporter-Mediated Uptake.
| العنوان: | Determination of Unbound Partition Coefficient and in Vitro-in Vivo Extrapolation for SLC13A Transporter-Mediated Uptake. |
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| المؤلفون: | Keith Riccardi, Zhenhong Li, Janice A Brown, Matthew F Gorgoglione, Mark Niosi, James Gosset, Kim Huard, Derek M Erion, Li Di, M F G, J G, K H, D M E |
| المساهمون: | The Pennsylvania State University CiteSeerX Archives |
| المصدر: | http://dmd.aspetjournals.org/content/dmd/44/10/1633.full.pdf. |
| سنة النشر: | 2016 |
| المجموعة: | CiteSeerX |
| الوصف: | Unbound partition coefficient (K puu ) is important to an understanding of the asymmetric free drug distribution of a compound between cells and medium in vitro, as well as between tissue and plasma in vivo, especially for transporter-mediated processes. K puu was determined for a set of compounds from the SLC13A family that are inhibitors and substrates of transporters in hepatocytes and transportertransfected cell lines. Enantioselectivity was observed, with (R)-enantiomers achieving much higher K puu (>4) than the (S)-enantiomers (<1) in human hepatocytes and SLC13A5-transfected human embryonic 293 cells. The intracellular free drug concentration correlated directly with in vitro pharmacological activity rather than the nominal concentration in the assay because of the high K puu mediated by SLC13A5 transporter uptake. Delivery of the diacid PF-06649298 directly or via hydrolysis of the ethyl ester prodrug PF-06757303 resulted in quite different K puu values in human hepatocytes (K puu of 3 for diacid versus 59 for prodrug), which was successfully modeled on the basis of passive diffusion, active uptake, and conversion rate from ester to diacid using a compartmental model. K puu values changed with drug concentrations; lower values were observed at higher concentrations possibly owing to a saturation of transporters. Michaelis-Menten constant (K m ) of SLC13A5 was estimated to be 24 mM for PF-06649298 in human hepatocytes. In vitro K puu obtained from rat suspension hepatocytes supplemented with 4% fatty acid free bovine serum albumin showed good correlation with in vivo K puu of liver-to-plasma, illustrating the potential of this approach to predict in vivo K puu from in vitro systems. |
| نوع الوثيقة: | text |
| وصف الملف: | application/pdf |
| اللغة: | English |
| Relation: | http://citeseerx.ist.psu.edu/viewdoc/summary?doi=10.1.1.1075.4018; http://dmd.aspetjournals.org/content/dmd/44/10/1633.full.pdf |
| الاتاحة: | http://citeseerx.ist.psu.edu/viewdoc/summary?doi=10.1.1.1075.4018 http://dmd.aspetjournals.org/content/dmd/44/10/1633.full.pdf |
| Rights: | Metadata may be used without restrictions as long as the oai identifier remains attached to it. |
| رقم الانضمام: | edsbas.41A203D6 |
| قاعدة البيانات: | BASE |
| الوصف غير متاح. |