کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
2478799 | 1113403 | 2014 | 8 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Utility of Cerebrospinal Fluid Drug Concentration as a Surrogate for Unbound Brain Concentration in Nonhuman Primates
ترجمه فارسی عنوان
سودمندی غلظت سیالات مغزی نخاعی به عنوان یک جایگزین برای غلظت مغز غیرمستقیم در افراد غیر انسانی
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کلمات کلیدی
موضوعات مرتبط
علوم پزشکی و سلامت
داروسازی، سم شناسی و علوم دارویی
اکتشاف دارویی
چکیده انگلیسی
In central nervous system drug discovery, cerebrospinal fluid (CSF) drug concentration (CCSF) has been widely used as a surrogate for unbound brain concentrations (Cu,brain). However, previous rodent studies demonstrated that when drugs undergo active efflux by transporters, such as P-glycoprotein (P-gp), at the blood-brain barrier, the CCSF overestimates the corresponding Cu,brain. To investigate the utility of CCSF as a surrogate for interstitial fluid (ISF) concentration (CISF) in nonhuman primates, this study simultaneously determined the CCSF and CISF of 12 compounds, including P-gp substrates, under steady-state conditions in cynomolgus monkeys using intracerebral microdialysis coupled with cisternal CSF sampling. Unbound plasma concentrations of non-or weak P-gp substrates were within 2.2-fold of the CISF or CCSF, whereas typical P-gp substrates (risperidone, verapamil, desloratadine, and quinidine) showed ISF-to-plasma unbound (Kp,uu,ISF) and CSF-to-plasma unbound concentration ratios (Kp,uu CSF) that were appreciably lower than unity. Although the Kp,uu,CSF of quinidine, verapamil, and desloratadine showed a trend of overestimating the Kp,uu,ISF, Kp,uu,csF showed a good agreement with Kp,uu,ISF within 3-fold variations for all compounds examined. Cu,brain of some basic compounds, as determined using brain homogenates, overestimated the CISF and CCSF. Therefore, CCSF could be used as a surrogate for CISF in nonhuman primates.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Drug Metabolism and Pharmacokinetics - Volume 29, Issue 5, 2014, Pages 419-426
Journal: Drug Metabolism and Pharmacokinetics - Volume 29, Issue 5, 2014, Pages 419-426
نویسندگان
Yoko Nagaya, Yoshitane Nozaki, Kazumasa Kobayashi, Osamu Takenaka, Yosuke Nakatani, Kazutomi Kusano, Tsutomu Yoshimura, Hiroyuki Kusuhara,