Severity: Warning
Message: fopen(/var/lib/php/sessions/ci_sessioni74koe3qpgfjn60bemo1jifob3k3puit): Failed to open stream: No space left on device
Filename: drivers/Session_files_driver.php
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File: /var/www/html/index.php
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Function: require_once
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Filename: Session/Session.php
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File: /var/www/html/index.php
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Function: require_once
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Message: Undefined array key "choices"
Filename: controllers/Detail.php
Line Number: 249
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File: /var/www/html/application/controllers/Detail.php
Line: 249
Function: _error_handler
File: /var/www/html/index.php
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Message: Trying to access array offset on value of type null
Filename: controllers/Detail.php
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File: /var/www/html/application/controllers/Detail.php
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Function: _error_handler
File: /var/www/html/index.php
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Message: Trying to access array offset on value of type null
Filename: controllers/Detail.php
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File: /var/www/html/application/controllers/Detail.php
Line: 249
Function: _error_handler
File: /var/www/html/index.php
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Message: Trying to access array offset on value of type null
Filename: controllers/Detail.php
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File: /var/www/html/application/controllers/Detail.php
Line: 249
Function: _error_handler
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Message: strpos(): Passing null to parameter #1 ($haystack) of type string is deprecated
Filename: models/Detail_model.php
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Function: strpos
File: /var/www/html/application/controllers/Detail.php
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Function: insertAPISummary
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Filename: helpers/my_audit_helper.php
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Function: str_replace
File: /var/www/html/application/controllers/Detail.php
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Function: formatAIDetailSummary
File: /var/www/html/index.php
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Message: Undefined array key "choices"
Filename: controllers/Detail.php
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File: /var/www/html/application/controllers/Detail.php
Line: 256
Function: _error_handler
File: /var/www/html/index.php
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Message: Trying to access array offset on value of type null
Filename: controllers/Detail.php
Line Number: 256
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File: /var/www/html/application/controllers/Detail.php
Line: 256
Function: _error_handler
File: /var/www/html/index.php
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Message: Trying to access array offset on value of type null
Filename: controllers/Detail.php
Line Number: 256
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File: /var/www/html/application/controllers/Detail.php
Line: 256
Function: _error_handler
File: /var/www/html/index.php
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Message: Undefined array key "usage"
Filename: controllers/Detail.php
Line Number: 257
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File: /var/www/html/application/controllers/Detail.php
Line: 257
Function: _error_handler
File: /var/www/html/index.php
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Message: Trying to access array offset on value of type null
Filename: controllers/Detail.php
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File: /var/www/html/application/controllers/Detail.php
Line: 257
Function: _error_handler
File: /var/www/html/index.php
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Message: Undefined array key "usage"
Filename: controllers/Detail.php
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File: /var/www/html/application/controllers/Detail.php
Line: 258
Function: _error_handler
File: /var/www/html/index.php
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Message: Trying to access array offset on value of type null
Filename: controllers/Detail.php
Line Number: 258
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File: /var/www/html/application/controllers/Detail.php
Line: 258
Function: _error_handler
File: /var/www/html/index.php
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Message: Undefined array key "usage"
Filename: controllers/Detail.php
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Filename: controllers/Detail.php
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Filename: controllers/Detail.php
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Function: _error_handler
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Filename: controllers/Detail.php
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Function: _error_handler
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Message: file_get_contents(https://...@gmail.com&api_key=61f08fa0b96a73de8c900d749fcb997acc09): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
Filename: helpers/my_audit_helper.php
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Function: file_get_contents
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Function: simplexml_load_file_from_url
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Function: pubMedGetRelatedKeyword
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Function: require_once
Objective: To study the combined effect of isoniazid and rifampicin on the activities of CYP1A2 and 3A4 in primary hepatocytes from healthy human adults.
Methods: The primary hepatocytes were isolated from adult healthy human livers, and cultured for 3 days. Then the cells were divided into 15 groups including two negative control groups (culture media alone) and 13 drug intervention groups, to which the following drugs were added: isoniazid (25 micromol/L, 50 micromol/L), rifampicin (12.5 micromol/L, 25 micromol/L) or both of them with different concentrations (CYP 1A2: rifampicin 12.5 micromol/L + isoniazid 50 micromol/L, rifampicin 25 micromol/L + isoniazid 50 micromol/L; CYP3A4: rifampicin 12.5 micromol/L + isoniazid 50 micromol/L, rifampicin 25 micromol/L + isoniazid 25 micromol/L, rifampicin 25 micromol/L + isoniazid 50 micromol/L) respectively. All the concentrations were consistent with the range of maximum clinical blood concentrations. After culture for 2 days, substrates (phenacetin for CYP1A2 , testosterone for CYP3A4) were added, and then the peak area (unit: mAU. min) of their metabolites was measured with high performance liquid chromatography (HPLC) to assess the activities of CYP450 1A2 and 3A4.
Results: (1) The activity of CYP1A2 in isoniazid groups with concentrations of 25 micromol/L and 50 micromol/L was (3.33 +/- 0.65), (3.03 +/- 0.38) mAU.min respectively, significantly different compared with that in the negative control group [(5.23 +/- 0.31) mAU.min, P < 0.01]. The activity of CYP450 1A2 in rifampicin groups with a concentration of 12.5 micromol/L was (6.07 +/- 0.55) mAU.min, which had significant difference compared with that in the negative control group (P < 0.05). There was no statistical difference of CYP1A2 activity between rifampicin with 25 micromol/L [(4.93 +/- 0.57) mAU.min] and the negative control group (P > 0.05). The activity of CYP1A2 of groups with two kinds of different concentrations of isoniazid and rifampicin combined groups was (3.27 +/- 0.96), (3.97 +/- 0.25) mAU.min respectively, which had significant difference compared with that in the negative control group (P < 0.05). (2) The activity of CYP3A4 in isoniazid groups with concentrations of 25 micromol/L and 50 micromol/L was (5.40 +/- 1.35), (2.63 +/- 0.06) mAU.min respectively, which had significant difference compared with that in the negative control group [(12.53 +/- 0.51) mAU.min, P < 0.01]. The activity of CYP3A4 in rifampicin groups with concentrations of 12.5 micromol/L and 25 micromol/L was (165.17 +/- 11.47), (120.20 +/- 15.73) mAU.min respectively, which had significant difference compared with that in the negative control group (P < 0.01). The activity of CYP3A4 in the three isoniazid and rifampicin combined groups with three kinds of different concentrations was (118.37 +/- 8.90), (77.53 +/- 6.91), (68.73 +/- 4.72) mAU.min respectively, which had significant difference compared with that in the negative control group (P < 0.01), but they were lower than those in rifampicin groups with corresponding concentrations (P < 0.05).
Conclusions: Isoniazid and rifampicin in the range of maximum clinical blood concentration have no significant inducing or inhibiting effect on the activity of CYP1A2 of healthy adult human primary hepatocytes. Isoniazid in the range of maximum clinical blood concentration can inhibit the activity of CYP3A4, while rifampicin can induce the activity of CYP3A4; the combined effect of isoniazid and rifampicin being the induction of CYP3A4 activity, but the inducing effect was less than that of rifampicin alone with the same concentration.
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