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	�:DEVELOPMENT AND VALIDATION OF A CHROMATOGRAPHIC METHOD FOR 
THE QUANTIFICATION OF ISONIAZID IN HUMAN PLASMA 

Authors and affiliations
Mohammed Alshaikheid1,2, Nadia Ben Fredj1, Amel Chaabane1, Zohra  Chadli1, Ahlem Slama1, Naceur Boughattas1, Mohamed Ali Lassoued1,2, Karim Aouam1

1Laboratory of Pharmacology, Faculty of Medicine of Monastir. 2Faculty of pharmacy of Monastir. Tunisia.


Corresponding author
Mohammed Alshaikheid
Laboratory of Pharmacology
Faculty of Medicine of Monastir
Rue Avicenne
5019 Monastir
Tunisia
Tel: 00 216-27531367
e-mail :  HYPERLINK "mailto:mohammed.alshaikheid@gmail.com" mohammed.alshaikheid@gmail.com
Mailing addresses of authors
Dr. Nadia Ben Fredj: benfredj.nadia@gmail.com
Dr. Amel Chaabane: dr.amelchaabane@gmail.com
Dr. Zohra  Chadli: zohrachadly@ymail.com
Ms. Ahlem Slama: slama.ahlem@yahoo.fr
Pr. Naceur Boughattas: naboughattas@yahoo.fr
Dr. Mohamed Ali Lassoued: lassoued98@yahoo.fr
Pr. Karim Aouam: aouam_k@yahoo.fr

Running head: Therapeutic drug monitoring of isoniazid

Abstract:
Objective: Isoniazid (INH) is a major antituberculosis treatment, characterized by a narrow therapeutic index and a large within and between-patient variability. Thus, Therapeutic Drug Monitoring (TDM) of this drug is mandatory in order to optimize the efficacy and minimize occurrence of toxic side effects of this drug. The aim of the present study is to develop and validate a simple chromatographic method for determination of INH in human plasma.
Methods: High performance liquid chromatography was performed using a chromatograph Ultimate 3000�. The extraction of INH from plasma was realized using trichloroacetic acid (TCA). Nicotinamide was used as an internal standard (IS). The mobile phase consisted of the buffer solution ammonium acetate (99%) 0.05 M adjusted by glacial acetic acid to pH 6 (99%), and acetonitrile (1%).  
The chromatographic separation was achieved on a C18 column (5�m, 4.6 x 150 mm) at 20��C. The signals were monitored by Diode Array Detector (DAD) at wavelength (�) of 265 nm, at a flow rate of 1.2 ml/min.
Results: The retention times of INH and IS were 6.4 and 10.5 respectively. The limits of detection and quantification of INH were 0.09 and 0.3 �g/ml, respectively. This present method is specific and linear over the range of 0.5 to 8 �g/ml with regression coefficient of 0.998. Additionally, this method is accurate and precise, as shown by appropriate statistical tests recommended for bioanalytical methods  validation.
Conclusion: we developed and validated a simple, rapid and convenient method for plasma INH determination in tuberculosis patients receiving this treatment.

KEYWORDS
Isoniazid;  Tuberculosis; High performance liquid chromatography; Analytical validation; Pharmacokinetic; Pharmacogenetic; Therapeutic drug monitoring.



1. INTRODUCTION
Tuberculosis or M. tuberculosis is currently a major global health problem as the last surveys conducted by the World Health Organization (WHO) have reported 10 million new tuberculosis cases and 1.8 million deaths worldwide1.
Isonicotinic acid hydrazide, known as isoniazid (INH), is one of the most important drugs, used in tuberculosis treatment as a first line antituberculosis chemotherapy since 1952[2,3].
This antituberculosis drug is characterized by a narrow therapeutic index and a large within and between-patient variability in both pharmacokinetics and pharmacodynamics[4].
This antituberculosis drug is characterized by a narrow therapeutic index and a large within and between-patient variability in both pharmacokinetics and pharmacodynamics. This variability among individuals has been attributed to several factors such as weight, age, gender and alcohol intake[5�7]. Moreover, variation in the pharmacokinetics of INH has been largely attributed to the activity of the enzymes that metabolize this drug; i.e; N-acetyltransferase2 (NAT2) and cytochrome P450 2E1 (CYP2E1) [8]. For these reasons, the dosage regimens of INH in clinical practice require a close Therapeutic Drug Monitoring (TDM) which aims to maximize efficacy and minimize the development of adverse effects. This approach is based on the determination of individual drug exposure and adjusting INHdose, accordingly, to achieve target therapeutic concentrations[6]. 
Several analytical methods aiming to determine INH plasma concentrations have been published previously, including chromatographic and non-chromatographic assays[9].  INH determination by non-chromatographic assays, such as spectrophotometric[10] and spectrofluorometric[11] procedures are known to have a lack of specificity and to be time consuming. Moreover, gas chromatography methods, used by many centers, are laborious and costly expensive. However, liquid chromatography is currently considered as a preferred method, since it is has the advantage to be accurate and could be suitable for the simultaneous measurement of other anti-tuberculosis drugs[4]. It is also recently used to study the phenotype of acetylation by some substances[12].
In the present study, we developed and validated a simple and convenient high performance liquid chromatographic method, allowing aselective and sensitive determination of INH concentration.

2. MATERIALS AND METHODS
Chemicals and reagents
Isoniazid pure powder was purchased from SIGMA-ALDRICH, India and Nicotinamide pure powder, used as internal standard (IS) was provided by SIGMA-ALDRICH, China. Purity for these compounds was more than 99%. Acetonitrile HPLC grade and ammonium acetate (NH4CH3CO2) was purchased from SUVCHEM, India. NaOH was obtained from SIGMA-ALDRICH, Netherlands and. Trichloroacetic acid (TCA) were purchased from SIGMA-ALDRICH, Germany. Glacial acetic acid was provided by Scharlab S.L. ,Spain. Water used for the preparation of the mobile phase was filtered through a 0.18 �m filter using an ultra-pure water system and the human plasma was and stored at a -20��C.
Equipments and conditions
High performance liquid chromatography was performed using a chromatograph Ultimate 3000 (Thermoscientific Germany Chromatographic separation was achieved using a C18 column (5�m, 4.6 x 150 mm). The mobile phase consisted of ammonium acetate (NH4CH3CO2) 0.05 M adjusted by glacial acetic acid to pH 6, and then filtered using 0.45-�m filter paper. Acetonitrile pumped using isocratic elution which achieved by using 99% of the ammonium acetate solution and 1% of acetonitrile. A flow rate of 1.2 mL/min was used. Injection volume of 80 �l was used with analysis time of 20 min. The column oven was set at 20��C. Signals were monitored by diode array detector at wavelength (�) of 265 nm. The concentration of INH was measured using the following equation: 
Height ratio = Height of INH peak/Height of IS peak
Solutions preparation
INH stock solution was prepared in distilled water at a concentration of 1g/L and stored at 4�C. INH working solution was prepared by a dilution of INH stock solution in distilled water at a concentration of 100 mg/L. Nicotinamide stock solution was prepared in distilled water at a concentration of 100�g/ml. The extraction solution consisted of nicotinamide prepared in a 10% TCA solution at a concentration of 50 �g/ml.


Samples collection
Five milliliters of venous blood samples were collected into a tube containing EDTA (ethylenediaminetetraacetic acid) at 3h after HRZE�(isoniazid, rifampin, pyrazinamide ethambutol) intake, and immediately sent to the Pharmacology Laboratory of the Faculty of Medicine of Monastir. The plasma samples were then separated by centrifugation and used for the determination of INH concentration.
Extraction procedures
One (1)�mL plasma was mixed with 500 �L of the extraction solution and vortexed for 30 seconds. Subsequently, the mixture was centrifuged at 3000 rpm for 15 min. The supernatant was neutralized by dilution with the same volume of (ammonium acetate (0.5 M), pH 8.2) and mixing by vortex and directly injected into the column.
Calibration curves
Five serum samples concentrations were used for INH calibration curve: 0.5, 1, 2, 4 and 8 �g/ml. Calibration curves were performed by plotting the height ratio of�INH/IS versus the respective points of INH concentration range (0.5-8 �g/ml).
Validation of the method 
The validation of INH dosing method was determined according to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use�(ICH) guidelines[13] and the reviewer guidance of the center for drug evaluation and research (CDER)[ ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"YfU6jU4o","properties":{"formattedCitation":"(13)","plainCitation":"(13)","dontUpdate":true},"citationItems":[{"id":295,"uris":["http://zotero.org/users/local/w9qgojuf/items/DS3AQBIP"],"uri":["http://zotero.org/users/local/w9qgojuf/items/DS3AQBIP"],"itemData":{"id":295,"type":"article","title":"UCM134409.pdf","URL":"https://www.fda.gov/downloads/Drugs/Guidances/UCM134409.pdf","accessed":{"date-parts":[["2017",6,27]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} 13]. We performed the following steps: specificity, limit of detection, limit of quantification, linearity, accuracy, repeatability and intermediate precision.
Specificity
The specificity of the present method was assessed by comparing the following three chromatograms: a chromatogram of the blank human plasma, a chromatogram of the spiked human plasma (4 �g/ml) and a chromatogram of one patient taking INH.

Detection limit
The detection limit consisted of the determination of the lowest concentration of INH which can be detected in a sample. It was calculated using the Signal-to-Noise method[ ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"vRDK1dMw","properties":{"formattedCitation":"(12)","plainCitation":"(12)","dontUpdate":true},"citationItems":[{"id":249,"uris":["http://zotero.org/users/local/w9qgojuf/items/Q249VRVW"],"uri":["http://zotero.org/users/local/w9qgojuf/items/Q249VRVW"],"itemData":{"id":249,"type":"article","title":"WC500002662.pdf","URL":"http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002662.pdf","accessed":{"date-parts":[["2017",2,4]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} 12].
Quantitation limit
It is defined by the lowest concentration of INH which can be reliably measured when compared with blank samples. Quantitation limit was determined using the Signal-to-Noise method according to ICH[13] .
Linearity
Three series of INH solution were reconstituted and analyzed over three successive days. Each series consisted of five concentration samples: 0.5, 1, 2, 4 and 8 �g/ml. Three successive injections were made and the mean of the responses was used to build the calibration curve.
The relation between height ratio (INH/IS) (y) and INH concentration (x) was expressed using the following linear regression equation:
y = ax +b; Where (a) The slope of the line, (b) the intercept 

Accuracy
The accuracy was evaluated by calculation of differences between the recovered concentrations of INH and the concentration in the pure INH solutions using the same procedures of injection in the linearity study. The mean recovery and its confidence interval were estimated.
Precision
The precision was assessed by the repeatability or intra-assay precision and intermediate precision. Three series of INH solutions were prepared and analyzed over three days. Each series contains six samples of the concentration 4	 �g/ml in order to study the method s repeatability on the same day and the intermediate precision over 3 days.
Statistical analysis:
Assessment of the linearity of the method was based on following statistical tests:1) the correlation coefficient (r) of the linear equation of height ratio vs INH concentration, 2) Student test for the comparison of the intercept with the 0; 3) test of homogeneity of variance using Cochran test, 4) Fisher test for regression line validity.
The accuracy of the method was evaluated using the following tests: homogeneity of variance by Cochran test, Test of the validity of the mean using Fisher test. 
The precision was evaluated by the determination of relative standard deviation (RSD) of repeatability ( QUOTE  ) and RSD of intermediate precision (RSDR). The accepted upper limit of RSD is 15%, as required by the Washington Conference for bioanalytical methods[14]. Besides, we performed the test for homogeneity of variance using Cochran test.
Application to patients� data
Isoniazid concentration was determined in patients diagnosed with pulmonary and extra-pulmonary tuberculosis at the University Hospital of Monastir (Tunisia), between February and December 2017, treated by first line antituberculosis treatment. 
During the antituberculosis treatment course, the isoniazid plasma concentration 3 hours after drug intake has been determined once at least for all patients. Acetylation phenotype was determined according to Vivien method [15] using the inactivation index of isoniazid (I3) which was calculated using the following equation:
I3 = (C3+0.60)/D, Where D: the administered dose in mg/kg.
According to Vivien�s method, patients were considered as slow acetylators or rapid acetylators, if I3 is greater than 0.65 or less than 0.65, respectively. The therapeutic range of concentration (C3) was between 1 and 2 �g/ml which allows the calculation of the lower effective dose (Dmin), the upper non toxic dose (Dmax) and the optimal recommended dose (Dr) according to the following equations:
Dmin= (1+0,6)/I3,  Dmax=(2+0,6)/I3  ,   Dr=2/I3 
3. RESULTS AND DISCUSSION:
Method development
The chosen mobile phase was composed of 1% acetonitrile and 99% ammonium acetate buffer solution. In order to determine the most suitable conditions of separation and detection of isoniazid, we have tested three flow rates (0.8, 1 and 1.2), three temperature ranges (18� C, 20� C and 25� C), and three volumes of injection (20 �l, 50 �l and 80 �l). Using the diode array detector, different wavelengths were assessed (275 nm, 248 nm, 261 nm and 265 nm).
The optimal separation conditions were as follows: a flow rate of 1.2 ml/min as it allows the minimization of the retention time (6.4 minutes) and the maintaining of a good resolution (figure 1). The optimal absorption wavelength for detection of INH was 265 nm. We chose a temperature of the column of 20�C as the peak symmetry was optimal. The injection volume of 80 �l was chosen to achieve the suitable peak height of INH and nicotinamide.
Method validation
Specificity
Three chromatogram profiles of blank human plasma, charged human plasma and patient�s plasma were compared, respectively. The chromatogram of the spiked human plasma and the chromatogram of the patient revealed two peaks of INH and nicotinamide. We note that INH and nicotinamide were well separated, with a retention time of 6.4 and 10.5, respectively. The chromatogram of the blank human plasma does not represent any peak that could interfere with the peak of INH or nicotinamide (Figure 1). Therefore, the present method could be considered as rapid and reliable since it needs a short run time with a sufficient separation quality, as compared with previous published protocols of HPLC isoniazid determination by L.A. Moussa et al.[4].
Detection limit
The detection limit of INH was 0.09 �g/ml with a signal-to-noise ratio of 3:1, considered as acceptable for determination of INH concentration according to ICH ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"vbr7pWCr","properties":{"formattedCitation":"(12)","plainCitation":"(12)","dontUpdate":true},"citationItems":[{"id":249,"uris":["http://zotero.org/users/local/w9qgojuf/items/Q249VRVW"],"uri":["http://zotero.org/users/local/w9qgojuf/items/Q249VRVW"],"itemData":{"id":249,"type":"article","title":"WC500002662.pdf","URL":"http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002662.pdf","accessed":{"date-parts":[["2017",2,4]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} 12.
Quantitation limit
The quantitation limit of INH was 0.3 �g/ml with a signal-to-noise ratio of 10:1. This concentration level, determined with accuracy and precision, is suitable for INH quantification in patients receiving this antituberculosis drug.
Linearity
Calibration curve of the five points of means (n = 3) for INH was linear over the concentration range of 0.5�8 �g/ml as shown in figure 2. 
According to Student test, the value of �t calculated� was less than the upper acceptance limit; i.e,� t(0,05;13)� . Thus, we can conclude that the intercept is not significantly different from �0� at the probability limit of p = 95% (Table 1). Test for homogeneity of variance, i.e; Cochran test, has shown that variances of the different levels for the INH are homogeneous, as �C calculated� was less than the upper limit of acceptance, i.e, �C(0,05,5,2)� ( Table 2). Assessment of regression line validity test using Fisher test has shown that adjustment error is not significantly different of experimental error (Table 3)
Thus, results of different statistical tests confirmed the linearity of the present method within a range of 0.5 to 8 mg/ml. 
Accuracy
Homogeneity of variances was confirmed using Cochran test (Table 4), so the variances considered homogenous at the 5% probability limit. Fisher test for the validity of means, has shown that �F calculated� is less than� F(0,05;4;10)))� at the confidence level of 95 % (table 5), so there are no significant differences between the inter-days means concentrations.
The calculated mean recovery was 98.58%, within the required accepted limit and the confidence interval (IC95 %) was [91,52%; 105,63%], included in the accepted interval for 95% of samples,  as required by the Washington Conference for bioanalytical methods[14].
Precision
The assessment of both intra-assay precision and intermediate precision using Cochran test has shown that the variances of different concentrations were homogeneous at 5% risk (Table 6). The calculated RSD of repeatability and intermediate precision were 13.56% and 14.17%, respectively. 
Application to patients� data:
One hundred thirty three (133) tuberculosis patients were included in the application. Eighty one (60.9 %) patients were slow acetylators and 52 patients (39.1 %) were rapid acetylators. The kinetic parameters of 133 patients were detailed in table 7.
The mean C3 was 2.52�1.35 �g/ml, ranging from 0.82 to 7.7�g/ml. Among 133 patients, 62 (46.61%) have shown a C3 in the normal range between 1 and 2�g/ml. sixty seven (50.38) have shown C3 more than 2�g/ml, they needed dose lowering to avoid toxicity while 4 patient have shown C3 less than 2�g/ml, therefore we made dose elevation to achieve drug efficacity.




4. CONCLUSION
In the present paper, we developed a simple and rapid DAD_HPLC method for determination of isoniazid in human plasma. The protocol developed in the current study was successfully validated as it was linear, sufficiently sensitive, accurate and precise, as shown by appropriate statistical tests recommended by ICH. Thus, this method could be suitable for routine INH determination and dosing adjustment in patients treated by combined anti-tuberculosis.

























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8.	Cho, H.-J. et al. (2007). Genetic polymorphisms of NAT2 and CYP2E1 associated with antituberculosis drug-induced hepatotoxicity in Korean patients with pulmonary tuberculosis. Tuberculosis 87, 551�556 
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����,�V"Corresponding authorMohammed AlshaikheidLaboratory of Pharmacology
Running head)Therapeutic drug monitoring of isoniazidWord count of the summary: 199Word count of the text: 1974Number of references: 14 Number of tables and figures: 7
Abstract:QObjective: Isoniazid is a major antituberculosis treatment, characterized by a nQMethods: High performance liquid chromatography was performed using a chromatogrQResults and discussion: The retention times of isoniazid and nicotinamide were 61. INTRODUCTION2. MATERIALS AND METHODSChemicals and reagentsMethod validationSpecificity
LinearityQCalibration curve of the five points of means (n = 3) for INH was linear over thUAccording to Student test, the value of “t calculated” was less than the upper aQThus, results of different statistical tests confirmed the linearity of the pres	AccuracyQHomogeneity of variances was confirmed using Cochran test (Table 4), so the variQThe calculated mean recovery was 98.58%, within the required accepted limit and QThe assessment of both intra-assay precision and intermediate precision using CoQEighty one (60.9 %) patients were slow acetylators and 52 patients (39.1 %) wereQIn the present paper, we developed a simple and rapid DAD_HPLC method for determQFigure 1: Chromatograms of (A) Spiked human plasma with INH and nicotinamide (ISKFigure 2: Calibration curve over the concentration range of 0.5–8 µg/mlTitleTitreTitres 0�����S[ � !"#	$
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data-version="3" zotero-version="4.0.29.10"><session id="n4Q0idpl"/><style id="http://www.zotero.org/styles/nature" hasBibliography="1" bibliographyStyleHasBeenSet="1"/><prefs><pref name="fieldType" value="Bookmark"/><pref name="storeReferences" valtue="true"/><pref name="automaticJournalAbbreviations" value="true"/><pref name="noteType" value=""/></prefs></data>,ZOTERO_BIBL {"custom":[]} CSL_BIBLIOGRAPHYZOTERO_ITEM CSL_CITATION {"citationID":"29s0aa7uq5","properties":{"formattedCitation":"{\\rtf \\super 1\\nosupersub{}}","plainCitation":"1"},"citationItems":[{"id":268,"uris":["http://zotero.org/users/local/w9qgojuf/items/WW8C5XE4"],"uri":["http://zotero.org/users/local/w9qgojuf/items/WW8C5XE4"],"itemData":{"id":268,"type":"webpage","title":"WHO | Tuberculosis","container-title":"WHO","abstract":"Tuberculosis is caused by bacteria that most often affect the lungs. TB is curable and preventable and is spre�ad from person to person through the air.","URL":"http://www.who.int/mediacentre/factsheets/fs104/en/","accessed":{"date-parts":[["2017",4,9]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}ZOTERO_ITEM CSL_CITATION {"citationID":"69274gt4u","properties":{"formattedCitation":"(Donald et al., 2007; Karimi, Mazloum-Ardakani, Mashhadizadeh, & Banifatemeh, 2009)","plainCitation":"(Donald et al., 2007; Karimi, Mazloum-Ardakani, Mashhadizadeh, & Banifatemeh, 2009)"},"citationItems":[{"id":25,"uris":["http://zotero.org/users/local/w9qgojuf/items/Q9WS85MF"],"uri":["http://zotero.org/users/local/w9qgojuf/items/Q9WS85MF"],"itemData":{"id":25,"type":"article-journal","title":"Simultaneous Kinetic Spectrophotometric Determination of Hydrazine and Isoniazid Using H-Point Standard Addition Method and Partial Least Squares Regression in Micellar Media","container-title":"ResearchGate","page":"729-738","volume":"82","issue":"4","source":"www.researchgate.net","abstract":"The present study describes the application of simultaneous kinetic spectrophotometric determination of hydrazine (HZ) and isoniazid (INH), using H-point standard addition method (HPSAM) and...","ISSN":"1334-417X","author":[{"family":"Karimi","given":"Mohammad Ali"},{"family":"Mazloum-Ardakani","given":"Mohammad"},{"family":"Mashhadizadeh","given":"Mohammad Hossein"},{"family":"Banifatemeh","given":"Fatemeh"}],"issued":{"date-parts":[["2009",12,1]]}}},{"id":62,"uris":["http://zotero.org/users/local/w9qgojuf/items/UZCHB343"],"uri":["http://zotero.org/users/local/w9qgojuf/items/UZCHB343"],"itemData":{"id":62,"type":"article-journal","title":"The influence of dose and N-acetyltransferase-2 (NAT2) genotype and phenotype on the pharmacokinetics and pharmacodynamics of isoniazid","container-title":"European Journal of Clinical Pharmacology","page":"633-639","volume":"63","issue":"7","source":"link.springer.com","abstract":"ObjectiveThis study evaluated the pharmacokinetics of isoniazid (INH) associated with optimal early bactericidal activity (EBA), defined as 90% of the maximum EBA (EBA90) and the influence of N-acetyltransferase-2 (NAT2) subtype on the ability of pulmonary tuberculosis (PTB) patients to reach the identified pharmacokinetic values after INH doses ranging from 0.2 to 10–12 mg/kg body weight.MethodsINH serum concentrations and NAT2 subtype were determined during four studies of PTB patients in three of whom the EBA of INH was determined. The relationship of EBA to area under the curve (AUC) (AUC0−∞)(AUC0−∞){\\left( {{\\text{AUC}}_{{0 - \\infty }} } \\right)} and 2-h serum concentrations was examined by exponential regression and fitted curves estimated the AUC0−∞AUC0−∞{\\text{AUC}}_{{0 - \\infty }} and 2-h serum concentrations at which EBA90 was reached.ResultsEBA90 was reached at an AUC0−∞AUC0−∞{\\text{AUC}}_{{0 - \\infty }} of 10.52 μg/ml per hour and 2-h serum concentrations of 2.19 μg/ml. An AUC0−∞AUC0−∞{\\text{AUC}}_{{0 - \\infty }} of 10.52 μg/ml per hour was reached by all 66 patients receiving a 10–12 mg/kg INH dose and all 21 receiving 6 mg/kg, except 1 of 10 (10%) homozygous fast (FF) acetylators; however, at 5 mg/kg, 4 of 12 (33%) FF and 26 of 27 (96%) heterozygous fast (FS), but all 21 homozygous slow (SS) acetylators did so; and 1 of 3 (33%) FF, 2 of 6 (33%) FS, but all 4 SS acetylators at dose 3 mg/kg. An INH 2-h serum concentration of 2.19 μg/ml was reached by all 66 patients receiving 10–12 mg/kg and all 21 receiving 6 mg/kg, except for 2 (20%) FF acetylators at a dose of 5 mg/kg; however, only 3 (25%) of 12 FF acetylators, but 26 (96%) of 27 FS acetylators, and all 21 SS acetylators reached this concentration; and at a dose of 3 mg/kg, 1 (33%) of 3 FF acetylators, 2 (33%) of 6 FF, but all 4 SS acetylators.ConclusionsAt a 6 mg/kg dose, all except a minority of FF NAT2 acetylators, achieve an INH AUC0−∞AUC0−∞{\\text{AUC}}_{{0 - \\infty }} and 2-h INH serum concentrations associated with EBA90, as did all 4 SS acetylators receiving 3 mg/kg. Any dose reduction below 6 mg/kg body weight will tend to disadvantage a significant proportion of faster acetylators, but, conversely, SS acetylators require only a 3 mg/kg dose to achieve a satisfactory exposure to INH.","DOI":"10.1007/s00228-007-0305-5","ISSN":"0031-6970, 1432-1041","journalAbbreviation":"Eur J Clin Pharmacol","language":"en","author":[{"family":"Donald","given":"P. R."},{"family":"Parkin","given":"D. P."},{"family":"Seifart","given":"H. I."},{"family":"Schaaf","given":"H. S."},{"family":"Helden","given":"P. D.","dropping-particle":"van"},{"family":"Werely","given":"C. J."},{"family":"Sirgel","given":"F. A."},{"family":"Venter","given":"A."},{"family":"Maritz","given":"J. S."}],"issued":{"date-parts":[["2007",5,16]]}}}],"schema":"https://github.com/citation-styl4e-language/schema/raw/master/csl-citation.json"}ZOTERO_ITEM CSL_CITATION {"citationID":"evj24kigj","properties":{"formattedCitation":"{\\rtf \\super 4\\nosupersub{}}","plainCitation":"4"},"citationItems":[{"id":247,"uris":["http://zotero.org/users/local/w9qgojuf/items/5QXGARXB"],"uri":["http://zotero.org/users/local/w9qgojuf/items/5QXGARXB"],"itemData":{"id":247,"type":"article-journal","title":"Therapeutic isoniazid monitoring using a simple high-performance liquid chromatographic method with ultraviolet detection","container-title":"Journal of Chromatography B","page":"181-187","volume":"766","issue":"1","source":"ScienceDirect","abstract":"Simultaneous measurement of isoniazid and its main acetylated metabolite acetylisoniazid in human plasma is realized by high-performance liquid chromatography. The technique used is evaluated by a factorial design of validation that proved to be convenient for routine drug monitoring. Plasma samples are deproteinized by trichloroacetic acid and then the analytes are separated on a μBondapak C18 column (Waters). Nicotinamide is used as an internal standard. The mobile phase is 0.05 M ammonium acetate buffer (pH 6)–acetonitrile (99:1, v/v). The detection is by ultraviolet absorbance at 275 nm. The validation, using the factorial design allows one to: (a) test the systematic factors of bias (linearity and matrix effect); (b) estimate the relative standard deviations (RSDs) related to extraction, measure and sessions assay. The linearity is confirmed to be within a range of 0.5 to 8 μg/ml of isoniazid and 1 to 16 μg/ml of acetylisoniazid. This method shows a good repeatability for both extraction and measurement (RSD INH=3.54% and 3.32%; RSD Ac.INH=0.00% and 5.97%), as well as a good intermediate precision (RSD INH=7.96%; RSD Ac.INH=15.86%). The method is also selective in cases of polytherapy as many drugs are associated (rifampicin, ethambutol, pyrazinamide, streptomycin). The matrix effect (plasma vs. water) is negligible for INH (3%), but statistically significant for Ac.INH (11%). The application of this validation design gave us the possibility to set up an easy and suitable method for INH therapeutic monitoring.","DOI":"10.1016/S0378-4347(01)00434-0","ISSN":"1570-0232","journalAbbreviation":"Journal of Chromatography B","author":[{"family":"Moussa","given":"L. Aı̈t"},{"family":"Khassouani","given":"C. E"},{"family":"Soulaymani","given":"R"},{"family":"Jana","given":"M"},{"family":"Cassanas","given":"G"},{"family":"Alric","given":"R"},{"family":"Hüe","given":"B"}],"issued":{"date-parts":[["2002",1,5]]}}}],"schemXa":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}ZOTERO_ITEM CSL_CITATION {"citationID":"ME0mhHQN","properties":{"formattedCitation":"{\\rtf \\super 5\\uc0\\u8211{}7\\nosupersub{}}","plainCitation":"5–7"},"citationItems":[{"id":163,"uris":["http://zotero.org/users/local/w9qgojuf/items/MP7B9JS6"],"uri":["http://zotero.org/users/local/w9qgojuf/items/MP7B9JS6"],"itemData":{"id":163,"type":"article-journal","title":"N-acetyl transferase 2 and cytochrome P450 2E1 genes and isoniazid-induced hepatotoxicity in Brazilian patients","container-title":"The International Journal of Tuberculosis and Lung Disease","page":"499-504","volume":"17","issue":"4","source":"IngentaConnect","abstract":"SETTING: Isoniazid (INH) is related to the development of hepatotoxicity in some patients.OBJECTIVE: To investigate the role of N-acetyl transferase 2 (NAT2) and cytochrome P450 2E1 (CYP2E1) in the hepatotoxicity of patients treated with INH in an Amazonian Brazilian population.DESIGN: Patients undergoing anti-tuberculosis treatment were investigated. Hepatotoxicity was defined as an increase of more than three times the upper limit of normal in serum alanine aminotransferase levels after treatment. NAT2 genotypes were identified by sequencing, whereas CYP2E1 alleles were detected using polymerase chain reaction based methods.RESULTS: Of the 270 individuals included in the study, 18 (6.7%) developed drug-related hepatotoxicity. A high association was found between slow acetylators and hepatotoxicity, particularly with regard to allele *5. The adjusted risk of developing hepatotoxicity was significant in individuals carrying two slow acetylation alleles (P = 0.036, OR 3.05, 95%CI 1.07–8.64). In all of the CYP2E1 markers examined, wild homozygous genotypes were more prevalent in subjects with hepatotoxicity than in controls; however, the difference was not statistically significant. Joint evaluation of the genes revealed a high risk of developing hepatotoxicity in slow acetylators with CYP2E1 wild alleles (adjusted OR 4.26; 95%CI 1.47–12.37, P = 0.008).CONCLUSIONS: Large-scale screening for NAT2 and CYP2E1 genotypes can prove useful in predicting the risk of adverse effects.","DOI":"10.5588/ijtld.12.0645","journalAbbreviation":"The International Journal of Tuberculosis and Lung Disease","author":[{"family":"Santos","given":"N. P. C."},{"family":"Callegari-Jacques","given":"S. M."},{"family":"Ribeiro dos Santos","given":"A. K. C."},{"family":"Silva","given":"C. A."},{"family":"Vallinoto","given":"A. C. R."},{"family":"Fernandes","given":"D. C. R. O."},{"family":"Carvalho","given":"D. C.","non-dropping-particle":"de"},{"family":"Santos","given":"S. E. B."},{"family":"Hutz","given":"M. H."}],"issued":{"date-parts":[["2013",4,1]]}}},{"id":23,"uris":["http://zotero.org/users/local/w9qgojuf/items/C96PN9CN"],"uri":["http://zotero.org/users/local/w9qgojuf/items/C96PN9CN"],"itemData":{"id":23,"type":"article-journal","title":"Risk factors of isoniazid-induced hepatotoxicity in Tunisian tuberculosis patients","container-title":"The Pharmacogenomics Journal","source":"PubMed","abstract":"Previous studies have shown controversial results on whether acetylator status causes isoniazid-induced hepatotoxicity (IIH). Moreover, the contribution of CYP2E1, a hepatic enzyme implicated in the formation of hepatotoxins, to the risk of developing IIH remains unclear. The objectives of this study were (i) to assess the quantitative relationship between the level of isoniazid serum concentration and the incidence of IIH and (ii) to evaluate the extent of implication of the N-acetyltransferase-2 (NAT2) and CYP2E1 polymorphisms genes to induce this disorder. Seventy-one patients with tuberculosis receiving a conventional antituberculosis regimen were included. NAT2 and CYP2E1 genotypes were determined using polymerase chain reaction. Three restriction enzymes, RsaI, PstI and DraI were used to detect CYP2E1 RFLP and four different restriction enzymes, KpnI, TaqI, BamHI and Ddel were used to determine NAT2 acetylator status. Therapeutic drug monitoring (TDM) of isoniazid (serum concentration performed 3 h after the morning dose: C3) was performed. Cases of isoniazid-induced hepatotoxicity were diagnosed according to Benichou et al. Receiver Operating Characteristics curve analysis was used to evaluate the relationship between risk factors and the incidence of IIH. Eleven (15.4%) patients have developed IIH. Demographic factors, including age, weight and gender were not associated with the incidence of hepatotoxicity. High serum concentration of isoniazid (C3) was found to be a risk factor of IIH (area under the curve: 0.74, P=0.007, 95% confidence interval (95% CI): 0.56-0.93), with a cutoff value at 3.69 mg l(-1) (odds ratio (OR): 13.2, P=0.0007, 95% CI: 2.9-59). Multivariate analysis showed that only a C3 over 3.69 mg l(-1) remains a risk factor of IIH. NAT2 and CYP2E1 variants were not found to increase the risk of IIH when analyzed separately. However, combined analysis of the NAT2/CYP2E1 gene polymorphisms showed that patients with both DraI C/D and slow acetylator have an increased risk of IIH compared with other combined NAT2/CYP2E1 genotype profiles (OR: 8.41, P=0.01, 95% CI: 1.54-45.76). Our results suggest that a serum concentration of isoniazid over 3.69 mg l(-1) and a combined genotype CYP2E1 DraI(C/D)/slow acetylator are major risk factors for IIH. Therefore, TDM of isoniazid and the determination of both NAT2 and CYP2E1 genotypes could be useful for the prediction and prevention of IIH in Tunisian tuberculosis patients.The Pharmacogenomics Journal advance online publication, 19 April 2016; doi:10.1038/tpj.2016.26.","DOI":"10.1038/tpj.2016.26","ISSN":"1473-1150","note":"PMID: 27089936","journalAbbreviation":"Pharmacogenomics J.","language":"ENG","author":[{"family":"Ben Fredj","given":"N."},{"family":"Gam","given":"R."},{"family":"Kerkni","given":"E."},{"family":"Chaabane","given":"A."},{"family":"Chadly","given":"Z."},{"family":"Boughattas","given":"N."},{"family":"Aouam","given":"K."}],"issued":{"date-parts":[["2016",4,19]]},"PMID":"27089936"}},{"id":301,"uris":["http://zotero.org/users/local/w9qgojuf/items/UHFS5RVQ"],"uri":["http://zotero.org/users/local/w9qgojuf/items/UHFS5RVQ"],"itemData":{"id":301,"type":"article-journal","title":"Pharmacokinetics of thrice-weekly rifampicin, isoniazid and pyrazinamide in adult tuberculosis patients in India","container-title":"The International Journal of Tuberculosis and Lung Disease: The Official Journal of the International Union Against Tuberculosis and Lung Disease","page":"1236-1241","volume":"20","issue":"9","source":"PubMed","abstract":"OBJECTIVE: To study the pharmacokinetics of rifampicin (RMP), isoniazid (INH) and pyrazinamide (PZA) in adult tuberculosis (TB) patients and examine factors that influence drug pharmacokinetics.\nMETHODS: Adult TB patients (n = 101) receiving thrice-weekly anti-tuberculosis treatment in the Revised National TB Control Programme (RNTCP) were studied. The study was conducted at steady state after directly observed drug administration. RMP, INH and PZA concentrations were estimated using high-performance liquid chromatography and NAT2 genotyping by real-time polymerase chain reaction.\nRESULTS: RMP peak concentration (Cmax) was sub-therapeutic (<8 μg/ml) in 88% of the patients. The Cmax of RMP, INH and PZA at 2 h was observed in respectively 83.2%, 97.0% and 92.1% of the patients. The Cmax and area under the curve from 0 to 8 h (AUC0-8) of PZA was lower in TB patients with diabetes mellitus than in non-diabetics. Significant associations were observed between the Cmax and the AUC0-8 of RMP, INH and PZA with drug doses; RMP with category of treatment; INH with smoking, body mass index and N-acetyl transferase 2 genotype; and PZA with sex and smoking.\nCONCLUSIONS: Several risk factors for drug concentration variations were identified. Two-hour post-dosing drug concentrations mimicked Cmax. A high proportion of TB patients had RMP Cmax below the expected range, which is a matter of concern.","DOI":"10.5588/ijtld.16.0048","ISSN":"1815-7920","note":"PMID: 27510252","journalAbbreviation":"Int. J. Tuberc. Lung Dis.","language":"eng","author":[{"family":"Hemanth Kumar","given":"A. K."},{"family":"Kannan","given":"T."},{"family":"Chandrasekaran","given":"V."},{"family":"Sudha","given":"V."},{"family":"Vijayakumar","given":"A."},{"family":"Ramesh","given":"K."},{"family":"Lava�nya","given":"J."},{"family":"Swaminathan","given":"S."},{"family":"Ramachandran","given":"G."}],"issued":{"date-parts":[["2016",9]]},"PMID":"27510252"}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}ZOTERO_ITEM CSL_CITATION {"citationID":"2eo681tehl","properties":{"formattedCitation":"{\\rtf \\super 8\\nosupersub{}}","plainCitation":"8"},"citationItems":[{"id":169,"uris":["http://zotero.org/users/local/w9qgojuf/items/6HX3JZZR"],"uri":["http://zotero.org/users/local/w9qgojuf/items/6HX3JZZR"],"itemData":{"id":169,"type":"article-journal","title":"Genetic polymorphisms of NAT2 and CYP2E1 associated with antituberculosis drug-induced hepatotoxicity in Korean patients with pulmonary tuberculosis","container-title":"Tuberculosis","page":"551-556","volume":"87","issue":"6","source":"ScienceDirect","abstract":"Summary\nAntituberculosis drug-induced hepatitis attributed to isoniazid (INH) is one of the most prevalent drug-induced liver injuries. INH is metabolized by hepatic N-acetyltransferase (NAT) and cytochrome P450 2E1 (CYP2E1) to form hepatotoxins. The aim of this study was to evaluate whether polymorphisms of the NAT2 and/or CYP2E1 genes were associated with antituberculosis drug-induced hepatotoxicity in Korean patients. A total of 132 patients with tuberculosis who received antituberculosis treatment were followed prospectively. Their NAT2 and CYP2E1 genotypes were determined using polymerase chain reaction (PCR) with or without sequencing. Eighteen (13.6%) patients developed antituberculosis drug-induced hepatotoxicity. Regarding NAT2, slow acetylators had a higher incidence of hepatotoxicity than rapid acetylators (36.8% vs. 9.7%, P=0.005) and there was a 3.8-fold risk of hepatotoxicity for the slow acetylators compared to the rapid acetylators. For the CYP2E1 gene, the RsaI polymorphism in the 5′ untranslated region, and a polymorphic repetitive sequence at the CYP2E1 5′-flaking region were analyzed; there was no significant association between any CYP2E1 genotype and antituberculosis drug-induced hepatotoxicity. In conclusion, slow acetylator status of NAT2 was a significant susceptibility risk factor for antituberculosis drug-induced hepatotoxicity; NAT2 genotyping may be a useful tool for predicting antituberculosis drug-induced hepatotoxicity.","DOI":"10.1016/j.tube.2007.05.012","ISSN":"1472-9792","journalAbbreviation":"Tuberculosis","author":[{"family":"Cho","given":"Hyun-Jung"},{"family":"Koh","given":"Won-Jung"},{"family":"Ryu","given":"Yon-Ju"},{"family":"Ki","given":"Chang-Seok"},{"family":"Nam","given":"Myung-Hyun"},{"family":"Kim","given":"Jong-Won"},{"family":"Lee","given":"Soo-Youn"}],"issued":{"date-parts":[["2007",11]]}}}],"schema":"https://github.com/citation-style-language/schema/ raw/master/csl-citation.json"}ZOTERO_ITEM CSL_CITATION {"citationID":"tjpgbm52h","properties":{"formattedCitation":"{\\rtf \\super 6\\nosupersub{}}","plainCitation":"6"},"citationItems":[{"id":23,"uris":["http://zotero.org/users/local/w9qgojuf/items/C96PN9CN"],"uri":["http://zotero.org/users/local/w9qgojuf/items/C96PN9CN"],"itemData":{"id":23,"type":"article-journal","title":"Risk factors of isoniazid-induced hepatotoxicity in Tunisian tuberculosis patients","container-title":"The Pharmacogenomics Journal","source":"PubMed","abstract":"Previous studies have shown controversial results on whether acetylator status causes isoniazid-induced hepatotoxicity (IIH). Moreover, the contribution of CYP2E1, a hepatic enzyme implicated in the formation of hepatotoxins, to the risk of developing IIH remains unclear. The objectives of this study were (i) to assess the quantitative relationship between the level of isoniazid serum concentration and the incidence of IIH and (ii) to evaluate the extent of implication of the N-acetyltransferase-2 (NAT2) and CYP2E1 polymorphisms genes to induce this disorder. Seventy-one patients with tuberculosis receiving a conventional antituberculosis regimen were included. NAT2 and CYP2E1 genotypes were determined using polymerase chain reaction. Three restriction enzymes, RsaI, PstI and DraI were used to detect CYP2E1 RFLP and four different restriction enzymes, KpnI, TaqI, BamHI and Ddel were used to determine NAT2 acetylator status. Therapeutic drug monitoring (TDM) of isoniazid (serum concentration performed 3 h after the morning dose: C3) was performed. Cases of isoniazid-induced hepatotoxicity were diagnosed according to Benichou et al. Receiver Operating Characteristics curve analysis was used to evaluate the relationship between risk factors and the incidence of IIH. Eleven (15.4%) patients have developed IIH. Demographic factors, including age, weight and gender were not associated with the incidence of hepatotoxicity. High serum concentration of isoniazid (C3) was found to be a risk factor of IIH (area under the curve: 0.74, P=0.007, 95% confidence interval (95% CI): 0.56-0.93), with a cutoff value at 3.69 mg l(-1) (odds ratio (OR): 13.2, P=0.0007, 95% CI: 2.9-59). Multivariate analysis showed that only a C3 over 3.69 mg l(-1) remains a risk factor of IIH. NAT2 and CYP2E1 variants were not found to increase the risk of IIH when analyzed separately. However, combined analysis of the NAT2/CYP2E1 gene polymorphisms showed that patients with both DraI C/D and slow acetylator have an increased risk of IIH compared with other combined NAT2/CYP2E1 genotype profiles (OR: 8.41, P=0.01, 95% CI: 1.54-45.76). Our results suggest that a serum concentration of isoniazid over 3.69 mg l(-1) and a combined genotype CYP2E1 DraI(C/D)/slow acetylator are major risk factors for IIH. Therefore, TDM of isoniazid and the determination of both NAT2 and CYP2E1 genotypes could be useful for the prediction and prevention of IIH in Tunisian tuberculosis patients.The Pharmacogenomics Journal advance online publication, 19 April 2016; doi:10.1038/tpj.2016.26.","DOI":"10.1038/tpj.2016.26","ISSN":"1473-1150","note":"PMID: 27089936","journalAbbreviation":"Pharmacogenomics J.","language":"ENG","author":[{"family":"Ben Fredj","given":"N."},{"family":"Gam","given":"R."},{"family":"Kerkni","given":"E."},{"family":"Chaabane","given":"A."},{"family":"Chadly","given":"Z."},{"family":"Boughattas","given":"N."},{"family":"Aouam","given":"K."}],"issued":{"date-parts":[["2016",4,19]]},"PMID":"27089936"}}],"schema":"https://github.com/citation-style-0language/schema/raw/master/csl-citation.json"}ZOTERO_ITEM CSL_CITATION {"citationID":"24s47iebea","properties":{"formattedCitation":"{\\rtf \\super 9\\nosupersub{}}","plainCitation":"9"},"citationItems":[{"id":282,"uris":["http://zotero.org/users/local/w9qgojuf/items/SWJJ3Z9S"],"uri":["http://zotero.org/users/local/w9qgojuf/items/SWJJ3Z9S"],"itemData":{"id":282,"type":"article-journal","title":"Chromatographic analysis of antituberculosis drugs in biological samples","container-title":"Journal of Chromatography B: Biomedical Sciences and Applications","collection-title":"Drug Level Monitoring","page":"321-359","volume":"340","source":"ScienceDirect","DOI":"10.1016/0378-4347(85)80201-2","ISSN":"0378-4347","journalAbbreviation":"Journal of Chromatography B: Biomedical Sciences and Applications","author�":[{"family":"Holdiness","given":"Mack R."}],"issued":{"date-parts":[["1985",5,10]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}ZOTERO_ITEM CSL_CITATION {"citationID":"HdgQ6kbb","properties":{"formattedCitation":"{\\rtf \\super 10\\nosupersub{}}","plainCitation":"10"},"citationItems":[{"id":303,"uris":["http://zotero.org/users/local/w9qgojuf/items/V3KJGTE4"],"uri":["http://zotero.org/users/local/w9qgojuf/items/V3KJGTE4"],"itemData":{"id":303,"type":"article-journal","title":"Spectrophotometric determination of isoniazid in presence of its hydrazones","container-title":"Journal of Pharmaceutical Sciences","page":"661-663","volume":"67","issue":"5","source":"PubMed","abstract":"A spectrophotometric determination of isoniazid in the presence of its hydrazones was developed. The method involves the reaction between isoniazid and 2,3-dichloro-1,4-naphthoquinone in the presence of ammonia in an ethanolic medium. The colored product has an absorbance maxium at 640 nm. The Lambert-Beer law is obeyed in the 1--14-microgram/ml range. The proposed method was applied to the analysis of isoniazid tablets. In commercial tablets, hydrazone formation due to the reaction between isoniazid and lactose was detected by TLC. The analysis of lactose-containing isoniazid tablets showed 10--22% lower recovery than that obtained by the official method. Hydrazone formation in tablets probably interferes with isoniazid bioavailability.","ISSN":"0022-3549","note":"PMID: 641804","journalAbbreviation":"J Pharm Sci","language":"eng","author":[{"family":"Devani","given":"M. B."},{"family":"Shishoo","given":"C. J."},{"family":"Patel","given":"M. A."},{"family":"B�halara","given":"D. D."}],"issued":{"date-parts":[["1978",5]]},"PMID":"641804"}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}ZOTERO_ITEM CSL_CITATION {"citationID":"6vDxpEJ3","properties":{"formattedCitation":"{\\rtf \\super 11\\nosupersub{}}","plainCitation":"11"},"citationItems":[{"id":281,"uris":["http://zotero.org/users/local/w9qgojuf/items/C7VVFCSK"],"uri":["http://zotero.org/users/local/w9qgojuf/items/C7VVFCSK"],"itemData":{"id":281,"type":"article","title":"a-novel-spectrofluorimetric-determination-of-four-antitb-drugs-in-their-pure-and-pharmaceutical-dosage-forms-by-quenching-effect-o.pdf","URL":"http://www.alliedacademies.org/articles/a-novel-spectrofluorimetric-determination-of-four-antitb-drugs-in-their-pure-and-pharmaceutical-dosage-forms-by-quenching-effect-o.pdf","accessed":{"date-parts":[["2017",4,10]]}}}],"schema":"https://github.com/citation-style-language/sche$ma/raw/master/csl-citation.json"}ZOTERO_ITEM CSL_CITATION {"citationID":"2j82hdrksl","properties":{"formattedCitation":"{\\rtf \\super 4\\nosupersub{}}","plainCitation":"4"},"citationItems":[{"id":247,"uris":["http://zotero.org/users/local/w9qgojuf/items/5QXGARXB"],"uri":["http://zotero.org/users/local/w9qgojuf/items/5QXGARXB"],"itemData":{"id":247,"type":"article-journal","title":"Therapeutic isoniazid monitoring using a simple high-performance liquid chromatographic method with ultraviolet detection","container-title":"Journal of Chromatography B","page":"181-187","volume":"766","issue":"1","source":"ScienceDirect","abstract":"Simultaneous measurement of isoniazid and its main acetylated metabolite acetylisoniazid in human plasma is realized by high-performance liquid chromatography. The technique used is evaluated by a factorial design of validation that proved to be convenient for routine drug monitoring. Plasma samples are deproteinized by trichloroacetic acid and then the analytes are separated on a μBondapak C18 column (Waters). Nicotinamide is used as an internal standard. The mobile phase is 0.05 M ammonium acetate buffer (pH 6)–acetonitrile (99:1, v/v). The detection is by ultraviolet absorbance at 275 nm. The validation, using the factorial design allows one to: (a) test the systematic factors of bias (linearity and matrix effect); (b) estimate the relative standard deviations (RSDs) related to extraction, measure and sessions assay. The linearity is confirmed to be within a range of 0.5 to 8 μg/ml of isoniazid and 1 to 16 μg/ml of acetylisoniazid. This method shows a good repeatability for both extraction and measurement (RSD INH=3.54% and 3.32%; RSD Ac.INH=0.00% and 5.97%), as well as a good intermediate precision (RSD INH=7.96%; RSD Ac.INH=15.86%). The method is also selective in cases of polytherapy as many drugs are associated (rifampicin, ethambutol, pyrazinamide, streptomycin). The matrix effect (plasma vs. water) is negligible for INH (3%), but statistically significant for Ac.INH (11%). The application of this validation design gave us the possibility to set up an easy and suitable method for INH therapeutic monitoring.","DOI":"10.1016/S0378-4347(01)00434-0","ISSN":"1570-0232","journalAbbreviation":"Journal of Chromatography B","author":[{"family":"Moussa","given":"L. Aı̈t"},{"family":"Khassouani","given":"C. E"},{"family":"Soulaymani","given":"R"},{"family":"Jana","given":"M"},{"family":"Cassanas","given":"G"},{"family":"Alric","given":"R"},{"family":"Hüe","given":"B"}],"issued":{"date-parts":[["2002",1,5]]}}}],"scheXma":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}ZOTERO_ITEM CSL_CITATION {"citationID":"2b6ckgs050","properties":{"formattedCitation":"{\\rtf \\super 12\\nosupersub{}}","plainCitation":"12"},"citationItems":[{"id":441,"uris":["http://zotero.org/users/local/w9qgojuf/items/6JSG2V8P"],"uri":["http://zotero.org/users/local/w9qgojuf/items/6JSG2V8P"],"itemData":{"id":441,"type":"article-journal","title":"A simple test for acetylator phenotype using caffeine.","container-title":"British Journal of Clinical Pharmacology","page":"459-464","volume":"17","issue":"4","source":"PubMed Central","abstract":"A method is presented for the use of caffeine, in the forms commonly ingested by a large proportion of the world's population, to test for the clinically important acetylation polymorphism. Each of 146 subjects provided a spot sample of urine between 2 and 6 h after coffee, tea or cola soft drink consumption, and the molar ratio of 5-acetylamino-6- formylamino -3-methyluracil ( AFMU ) to 1-methylxanthine (1X) was determined by a simple h.p.l.c. assay. The ratio afforded segregation of three apparent modes of acetylation capacity in this population, in concordance with a standard sulphamethazine phenotyping procedure and with other methods using controlled caffeine intake and urine collections. The day-to-day consistency of the method was established in eight selected subjects.","ISSN":"0306-5251","note":"PMID: 6721992\nPMCID: PMC1463406","journalAbbreviation":"Br J Clin Pharmacol","author":[{"family":"Grant","given":"D M"},{"family":"Tang","given":"B K"},{"family"�:"Kalow","given":"W"}],"issued":{"date-parts":[["1984",4]]},"PMID":"6721992","PMCID":"PMC1463406"}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}ZOTERO_ITEM CSL_CITATION {"citationID":"LFUXJTnZ","properties":{"formattedCitation":"{\\rtf \\super 13\\nosupersub{}}","plainCitation":"13"},"citationItems":[{"id":249,"uris":["http://zotero.org/users/local/w9qgojuf/items/Q249VRVW"],"uri":["http://zotero.org/users/local/w9qgojuf/items/Q249VRVW"],"itemData":{"id":249,"type":"article","title":"WC500002662.pdf","URL":"http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002662.pdf","accessed":{"date-parts":[["2017",2,4]]}}}]\,"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}ZOTERO_ITEM CSL_CITATION {"citationID":"jOB9KKbs","properties":{"formattedCitation":"{\\rtf \\super 13\\nosupersub{}}","plainCitation":"13"},"citationItems":[{"id":249,"uris":["http://zotero.org/users/local/w9qgojuf/items/Q249VRVW"],"uri":["http://zotero.org/users/local/w9qgojuf/items/Q249VRVW"],"itemData":{"id":249,"type":"article","title":"WC500002662.pdf","URL":"http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002662.pdf","accessed":{"date-parts":[["2017",2,4]]}}}]\,"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}ZOTERO_ITEM CSL_CITATION {"citationID":"okISzkHM","properties":{"formattedCitation":"{\\rtf \\super 14\\nosupersub{}}","plainCitation":"14"},"citationItems":[{"id":289,"uris":["http://zotero.org/users/local/w9qgojuf/items/5W938G4K"],"uri":["http://zotero.org/users/local/w9qgojuf/items/5W938G4K"],"itemData":{"id":289,"type":"article-journal","title":"An analysis of the Washington Conference Report on bioanalytical method validation","container-title":"Journal of Pharmaceutical and Biomedical Analysis","page":"1337-1343","volume":"12","issue":"11","source":"PubMed","abstract":"The Washington Conference Report on bioanalytical method validation is analysed with respect to the requirements for precision and accuracy. It is shown that if the requirements are interpreted too literally, this could lead to disappointment in practice. A better approach is to separate the total measurement error into its constant (bias) and random (precision) components. To ensure that 95% of all methods fall within the acceptance interval of +/- 15% around the true value, would require, for example, the bias to be < or = 8% and the method precision to be < or = 8% relative standard deviation (RSD; n = 5).","ISSN":"0731-7085","note":"PMID: 7849129","journalAbbreviation":"J Pharm Biomed Anal","language":"eng","author":[{"family":"Hartmann","given":"C."},{"family":"Massart","given":"D. L."},{"family":"McDowall","given":"R. 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The technique used is evaluated by a factorial design of validation that proved to be convenient for routine drug monitoring. Plasma samples are deproteinized by trichloroacetic acid and then the analytes are separated on a μBondapak C18 column (Waters). Nicotinamide is used as an internal standard. The mobile phase is 0.05 M ammonium acetate buffer (pH 6)–acetonitrile (99:1, v/v). The detection is by ultraviolet absorbance at 275 nm. The validation, using the factorial design allows one to: (a) test the systematic factors of bias (linearity and matrix effect); (b) estimate the relative standard deviations (RSDs) related to extraction, measure and sessions assay. The linearity is confirmed to be within a range of 0.5 to 8 μg/ml of isoniazid and 1 to 16 μg/ml of acetylisoniazid. This method shows a good repeatability for both extraction and measurement (RSD INH=3.54% and 3.32%; RSD Ac.INH=0.00% and 5.97%), as well as a good intermediate precision (RSD INH=7.96%; RSD Ac.INH=15.86%). The method is also selective in cases of polytherapy as many drugs are associated (rifampicin, ethambutol, pyrazinamide, streptomycin). The matrix effect (plasma vs. water) is negligible for INH (3%), but statistically significant for Ac.INH (11%). The application of this validation design gave us the possibility to set up an easy and suitable method for INH therapeutic monitoring.","DOI":"10.1016/S0378-4347(01)00434-0","ISSN":"1570-0232","journalAbbreviation":"Journal of Chromatography B","author":[{"family":"Moussa","given":"L. Aı̈t"},{"family":"Khassouani","given":"C. 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It is shown that if the requirements are interpreted too literally, this could lead to disappointment in practice. A better approach is to separate the total measurement error into its constant (bias) and random (precision) components. To ensure that 95% of all methods fall within the acceptance interval of +/- 15% around the true value, would require, for example, the bias to be < or = 8% and the method precision to be < or = 8% relative standard deviation (RSD; n = 5).","ISSN":"0731-7085","note":"PMID: 7849129","journalAbbreviation":"J Pharm Biomed Anal","language":"eng","author":[{"family":"Hartmann","given":"C."},{"family":"Massart","given":"D. L."},{"family":"McDowall","given":"R. D."}],"issued":{"date-parts":[["1994",11]]},"PMID":"7849129"}}],"schema":"https://github.com/citation-style-lang,uage/schema/raw/master/csl-citation.json"},ZOTERO_BIBL {"custom":[]} CSL_BIBLIOGRAPHYZOTERO_TEMPZOTERO_TEMPZOTERO_ITEM CSL_CITATION {"citationID":"2h88qh093e","properties":{"formattedCitation":"{\\rtf \\super 2,3\\nosupersub{}}","plainCitation":"2,3"},"citationItems":[{"id":62,"uris":["http://zotero.org/users/local/w9qgojuf/items/UZCHB343"],"uri":["http://zotero.org/users/local/w9qgojuf/items/UZCHB343"],"itemData":{"id":62,"type":"article-journal","title":"The influence of dose and N-acetyltransferase-2 (NAT2) genotype and phenotype on the pharmacokinetics and pharmacodynamics of isoniazid","container-title":"European Journal of Clinical Pharmacology","page":"633-639","volume":"63","issue":"7","source":"link.springer.com","abstract":"ObjectiveThis study evaluated the pharmacokinetics of isoniazid (INH) associated with optimal early bactericidal activity (EBA), defined as 90% of the maximum EBA (EBA90) and the influence of N-acetyltransferase-2 (NAT2) subtype on the ability of pulmonary tuberculosis (PTB) patients to reach the identified pharmacokinetic values after INH doses ranging from 0.2 to 10–12 mg/kg body weight.MethodsINH serum concentrations and NAT2 subtype were determined during four studies of PTB patients in three of whom the EBA of INH was determined. The relationship of EBA to area under the curve (AUC) (AUC0−∞)(AUC0−∞){\\left( {{\\text{AUC}}_{{0 - \\infty }} } \\right)} and 2-h serum concentrations was examined by exponential regression and fitted curves estimated the AUC0−∞AUC0−∞{\\text{AUC}}_{{0 - \\infty }} and 2-h serum concentrations at which EBA90 was reached.ResultsEBA90 was reached at an AUC0−∞AUC0−∞{\\text{AUC}}_{{0 - \\infty }} of 10.52 μg/ml per hour and 2-h serum concentrations of 2.19 μg/ml. An AUC0−∞AUC0−∞{\\text{AUC}}_{{0 - \\infty }} of 10.52 μg/ml per hour was reached by all 66 patients receiving a 10–12 mg/kg INH dose and all 21 receiving 6 mg/kg, except 1 of 10 (10%) homozygous fast (FF) acetylators; however, at 5 mg/kg, 4 of 12 (33%) FF and 26 of 27 (96%) heterozygous fast (FS), but all 21 homozygous slow (SS) acetylators did so; and 1 of 3 (33%) FF, 2 of 6 (33%) FS, but all 4 SS acetylators at dose 3 mg/kg. An INH 2-h serum concentration of 2.19 μg/ml was reached by all 66 patients receiving 10–12 mg/kg and all 21 receiving 6 mg/kg, except for 2 (20%) FF acetylators at a dose of 5 mg/kg; however, only 3 (25%) of 12 FF acetylators, but 26 (96%) of 27 FS acetylators, and all 21 SS acetylators reached this concentration; and at a dose of 3 mg/kg, 1 (33%) of 3 FF acetylators, 2 (33%) of 6 FF, but all 4 SS acetylators.ConclusionsAt a 6 mg/kg dose, all except a minority of FF NAT2 acetylators, achieve an INH AUC0−∞AUC0−∞{\\text{AUC}}_{{0 - \\infty }} and 2-h INH serum concentrations associated with EBA90, as did all 4 SS acetylators receiving 3 mg/kg. Any dose reduction below 6 mg/kg body weight will tend to disadvantage a significant proportion of faster acetylators, but, conversely, SS acetylators require only a 3 mg/kg dose to achieve a satisfactory exposure to INH.","DOI":"10.1007/s00228-007-0305-5","ISSN":"0031-6970, 1432-1041","journalAbbreviation":"Eur J Clin Pharmacol","language":"en","author":[{"family":"Donald","given":"P. R."},{"family":"Parkin","given":"D. P."},{"family":"Seifart","given":"H. I."},{"family":"Schaaf","given":"H. S."},{"family":"Helden","given":"P. D.","dropping-particle":"van"},{"family":"Werely","given":"C. J."},{"family":"Sirgel","given":"F. A."},{"family":"Venter","given":"A."},{"family":"Maritz","given":"J. S."}],"issued":{"date-parts":[["2007",5,16]]}}},{"id":25,"uris":["http://zotero.org/users/local/w9qgojuf/items/Q9WS85MF"],"uri":["http://zotero.org/users/local/w9qgojuf/items/Q9WS85MF"],"itemData":{"id":25,"type":"article-journal","title":"Simultaneous Kinetic Spectrophotometric Determination of Hydrazine and Isoniazid Using H-Point Standard Addition Method and Partial Least Squares Regression in Micellar Media","container-title":"ResearchGate","page":"729-738","volume":"82","issue":"4","source":"www.researchgate.net","abstract":"The present study describes the application of simultaneous kinetic spectrophotometric determination of hydrazine (HZ) and isoniazid (INH), using H-point standard addition method (HPSAM) and...","ISSN":"1334-417X","author":[{"family":"Karimi","given":"Mohammad Ali"},{"family":"Mazloum-Ardakani","given":"Mohammad"},{"family":"Mashhadizadeh","given":"Mohammad Hossein"},{"f�amily":"Banifatemeh","given":"Fatemeh"}],"issued":{"date-parts":[["2009",12,1]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}	

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