Severity: Warning
Message: file_get_contents(https://...@pubfacts.com&api_key=b8daa3ad693db53b1410957c26c9a51b4908&a=1): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
Filename: helpers/my_audit_helper.php
Line Number: 176
Backtrace:
File: /var/www/html/application/helpers/my_audit_helper.php
Line: 176
Function: file_get_contents
File: /var/www/html/application/helpers/my_audit_helper.php
Line: 250
Function: simplexml_load_file_from_url
File: /var/www/html/application/helpers/my_audit_helper.php
Line: 3122
Function: getPubMedXML
File: /var/www/html/application/controllers/Detail.php
Line: 575
Function: pubMedSearch_Global
File: /var/www/html/application/controllers/Detail.php
Line: 489
Function: pubMedGetRelatedKeyword
File: /var/www/html/index.php
Line: 316
Function: require_once
Drugs containing the carboxylic functional group can be metabolized to form acylglucuronides believed to cause idiosyncratic drug toxicity when the acylglucuronide is unstable. Recent studies have shown that the half-life of an acylglucuronide in phosphate buffer is the best means for classifying acylglucuronides into safe, warning, and withdrawn drugs. However, it is difficult to halt the late stage development of new chemical entities due to the instability of their acylglucuronides. We report an optimized in vitro method for determining the half-lives of acylglucuronides in simple phosphate buffer without the need for authentic standards. The experiment was divided into two incubations. In the first incubation, acylglucuronide was synthesized by human liver microsomes, and in the second incubation, the degradation rate of acylglucuronide in phosphate buffer was determined. The degradation rate constants of acylglucuronides were determined from changes in the LC-MS/MS peak area and the half-lives were calculated. We evaluated the half-lives of 10 drugs: 3 safe drugs (telmisartan, gemfibrozil and flufenamic acid) and 7 withdrawn or warning drugs (zomepirac, diclofenac, furosemide, ibuprofen, S-naproxen, probenecid and tolmetin). The half-lives of the 3 safe drugs were 10.6 h or longer, whereas the half-lives of the 7 withdrawn or warning drugs were 4.0 h or shorter. Although authentic acylglucuronide standards were not used, we obtained half-lives of acylglucuronides in phosphate buffer similar to those reported previously. Using this method, the risk of reactivity caused by acylglucuronides can be evaluated in the early stages of drug discovery.
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Source |
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http://dx.doi.org/10.1248/bpb.b13-00329 | DOI Listing |
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