کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
9917726 | 1556310 | 2005 | 9 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
The role of physicochemical properties of entacapone and tolcapone on their efficacy during local intrastriatal administration
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کلمات کلیدی
موضوعات مرتبط
علوم پزشکی و سلامت
داروسازی، سم شناسی و علوم دارویی
اکتشاف دارویی
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چکیده انگلیسی
Aqueous solubility, apparent partition coefficient (log Papp) and catechol-O-methyltransferase (COMT, EC 2.1.1.6) inhibiting potency of entacapone and tolcapone were compared in vitro. Both drugs (at 10 and 100 μM) were also delivered directly into rat striatum via a microdialysis probe. Extracellular 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) concentrations were measured to evaluate the inhibition of striatal COMT in vivo. Although entacapone had 15-fold better aqueous solubility than tolcapone at pH 7.4, also tolcapone had sufficient aqueous solubility to remain in solution at 100 μM. The log Papp of tolcapone was higher than that reported for entacapone in the pH range from 5.0 to 7.4. Entacapone and tolcapone inhibited equally rat striatal COMT in vitro with Ki values of 1.86 and 2.50 nM, respectively. Both drugs had similar outflow from the microdialysis probe in vitro. Perfusion of 100 μM entacapone increased significantly extracellular DOPAC levels compared to the control group. Both entacapone and tolcapone (at 10 and 100 μM) decreased significantly HVA levels, but entacapone was significantly more effective than tolcapone at 100 μM. In conclusion, entacapone and tolcapone are equally potent COMT inhibitors against rat striatal COMT in vitro. After local intrastriatal administration, entacapone appeared to inhibit COMT faster and more effectively than the more lipophilic tolcapone. Thus, intrastriatal administration led to opposite results compared to those reported in the brain after systemic administration. The present results also suggest that the local distribution of entacapone and tolcapone differ when the drugs are delivered directly into the brain.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: European Journal of Pharmaceutical Sciences - Volume 24, Issue 5, April 2005, Pages 503-511
Journal: European Journal of Pharmaceutical Sciences - Volume 24, Issue 5, April 2005, Pages 503-511
نویسندگان
Markus M. Forsberg, Marko Huotari, Jouko Savolainen, Pekka T. Männistö,