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Tao HuangMedical School, Huanghe Science and Technology University, Zhengzhou, Henan Province 450063, PR China

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Li WangMedical School, Huanghe Science and Technology University, Zhengzhou, Henan Province 450063, PR China

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Fang WangSchool of Medicine, Shaanxi Energy Institute, Xianyang, Shaanxi Province 712000, PR China

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Xin ShenDepartment of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, PR China

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Libin WangMedical School, Huanghe Science and Technology University, Zhengzhou, Henan Province 450063, PR China
School of Medicine, Shaanxi Energy Institute, Xianyang, Shaanxi Province 712000, PR China

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Abstract

In the present study, an LC-MS/MS method allowing to quantify pretomanid and pyrazinamide simultaneously in rat plasma was developed. Chromatographic separation was achieved on an Agilent Eclipse plus C18 column (100 mm × 2.1 mm, 3.5 μm; Agilent, USA) and maintained at 30 °C. Multiple reaction monitoring (MRM) using positive-ion ESI mode to monitor ion transitions of m/z 360.1 → m/z 175.1 for pretomanid, m/z 124.1 → m/z 81.0 for pyrazinamide, m/z 172.1 → m/z 128.1 for metronidazole (IS). The calibration curves showed good linear relationships over the concentration range of 50–7,500 ng mL−1 for pretomanid and 500–75,000 ng mL−1 for pyrazinamide. The precision and accuracy were below 15% and within ±15% of the nominal concentrations, respectively. The selectivity, recovery and matrix effect of this method were all within acceptable limits of bioanalytics. The method was applied to the analysis of plasma samples from pharmacokinetic studies in rats. The results show that the main pharmacokinetic parameters of pyrazinamide, namely, T max, t 1/2, and AUC(0–t), decreased in the combined group than in the alone group.

Abstract

In the present study, an LC-MS/MS method allowing to quantify pretomanid and pyrazinamide simultaneously in rat plasma was developed. Chromatographic separation was achieved on an Agilent Eclipse plus C18 column (100 mm × 2.1 mm, 3.5 μm; Agilent, USA) and maintained at 30 °C. Multiple reaction monitoring (MRM) using positive-ion ESI mode to monitor ion transitions of m/z 360.1 → m/z 175.1 for pretomanid, m/z 124.1 → m/z 81.0 for pyrazinamide, m/z 172.1 → m/z 128.1 for metronidazole (IS). The calibration curves showed good linear relationships over the concentration range of 50–7,500 ng mL−1 for pretomanid and 500–75,000 ng mL−1 for pyrazinamide. The precision and accuracy were below 15% and within ±15% of the nominal concentrations, respectively. The selectivity, recovery and matrix effect of this method were all within acceptable limits of bioanalytics. The method was applied to the analysis of plasma samples from pharmacokinetic studies in rats. The results show that the main pharmacokinetic parameters of pyrazinamide, namely, Tmax, t1/2, and AUC(0–t), decreased in the combined group than in the alone group.

1 Introduction

Tuberculosis (TB) remains a major global public health threat, infecting and killing mainly in developing countries [1, 2]. The reason why TB is so difficult to treat is because of the TB bacterium's three “weapons”: persistence [3], drug resistance [4] and virulence [5]. Among them, the infection of drug-resistant Mycobacterium tuberculosis (MTB) is a major difficulty in TB control [6]. In 2018, the world health organization (WHO) estimates that at least 6.3 million new cases of TB caused by pyrazinamide and fluoroquinolone are reported, including 490,000 cases of multidrug-resistant (MDR) -TB [7]. In addition, due to the increasing incidence of MDR and extensively drug-resistant (XDR) -TB, there are limited antibiotic options available to treat TB [8]. Therefore, there is an urgent need to develop new drugs, find new targets and new combinations of treatment methods to cope with the growing trend of TB.

Due to the great resistance to first-line drugs, XDR-TB and MDR-TB are often difficult to cure completely [9]. Pretomanid is one of the preferred drugs evaluated in clinical trials for the treatment of drug-resistant MTB [10]. By inhibiting cell wall formation and respiratory toxicity, pretomanid shows significant bactericidal activity against both replicative and stationary MTB [11]. The combination of pretomanid, bedaquinoline and linezolid, which has synergistic or additive potential in killing bacteria and inhibiting drug resistance, is also described, and is expected to further improve current TB treatment outcomes [12].

Among the first-line anti-TB drugs, pyrazinamide can kill MTB and retain bacteria in the semi-dormant period under acidic conditions [13]. And pyrazinamide can shorten the treatment time of TB from 9–12 months to 6 months [14], so it plays an important role in shortening the treatment time in short-course chemotherapy of TB. Although pyrazinamide can completely eradicate TB, it has obvious disadvantages in clinical application. Compared with other first-line anti-TB drugs (such as isoniazid in vitro MIC value of 0.061 μg mL−1, rifampicin in vitro MIC Value is 60 μg mL−1), in vitro MIC value of pyrazinamide (50–120 μg mL−1) is high, so it must be administered in large doses to play a therapeutic role, long-term large doses of pyrazinamide will cause significant liver toxicity [15].

At present, there is experimental evidence suggests that the new drug pretomanid combined with pyrazinamide, may assist treatment shortening of drug-susceptible and XDR-TB [16]. In the current work, we conducted studies to characterize the potential for a pharmacokinetic interaction between pretomanid and pyrazinamide in rats using LC-MS/MS. We have developed and validated an LC-MS/MS method for the simultaneous determination of pretomanid and pyrazinamide in rat plasma. It was then applied to the pharmacokinetic interaction study in rats with simple protein precipitation method as sample preparation approach. Significant differences in pharmacokinetic properties of pyrazinamide were observed between the alone and combined groups after administration of equal dose of pretomanid and pyrazinamide.

2 Experimental

2.1 Materials and reagents

Pretomanid, pyrazinamide and metronidazole (IS) were purchased from Sigma-Aldrich (St. Louis, MO, USA). Methanol and acetonitrile were of MS grade (Tedia Co. Inc., Ohio OH, USA). Milli-Q water was used throughout the whole experiments (Millipore, Bedford, MA, USA). Other solvents used for analysis were of analytical grade.

2.2 Animals

Sprague-Dawley rats (250 ± 20 g) were purchased from the Experimental Animal Center, Air Force Military Medical University (Shaanxi, China). All the experimental protocols were approved by the Guidelines for the Care and Use of Laboratory Animals. Rats were acclimated in the laboratory for one week prior to the experiments, housed separately in a metabolic cage at a temperature of 23 ± 2 °C with a relative humidity of 50% and a 12 h light/dark cycle, free access to standard water and diet. The rats were fasted for 12 h before oral administration with free access to water.

2.3 Drug administration and sampling

In the pharmacokinetic study, 24 rats were randomly divided into three groups (n = 8 per group), each group were orally administered Pretomanid (20 mg mL−1), pyrazinamide (150 mg mL−1), and Pretomanid (20 mg mL−1) plus pyrazinamide (150 mg mL−1), respectively. Blood samples (0.3 mL) were collected via retro-orbital puncture at 5, 15, 30, 60, 120, 180, 240, 360, 480, 720, 1,080, 1,440, 2,160 min post-dosing after the rats were orally administered. Then, each blood sample was immediately centrifuged at approximately 10,000 rpm, 4 °C for 10 min and a 100 µL aliquot of supernatant plasma layer was transferred into another tube and stored at −80 °C until analysis. An aliquot of 100 µL rat plasma sample was mixed with 10 µL of internal standard solution (1 μg mL−1), 800 µL acetonitrile were added. The sample was vortexmixed for 5 min, and the mixture was separated by centrifugating at 10,000 rpm for 10 min. An aliquot of 500 µL of the protein-free supernatant was then evaporated to dryness at 40 °C under nitrogen. The resulting extract was dissolved in 50 µL of methanol, and vortexmixed for 3 min. After centrifugation at 10,000 rpm for 10 min, an aliquot of 5 µL supernatant was injected into the LC-MS.

2.4 Preparation of stock solutions

All compounds were dissolved by methanol (1 mg mL−1). These stock solutions were diluted with methanol to obtain calibration solutions. Internal standard solution was prepared by dilution of stock solution to a concentration of 50 ng mL−1. All the solutions were stored at −20 °C and were brought to room temperature before use.

2.5 LC-MS/MS analysis

The liquid chromatography was performed on a Shimadzu HPLC, which included a LC-30AD binarypump, an online vacuum degasser, an autosampler, and a columnoven (Shimadzu, Kyoto, Japan). The LC system was coupled with an API 4,000 tandem mass spectrometer (Applied Biosystems/MDS SCIEX, USA) equipped with an electrospray ionization source. Data were collected and analyzed by Analyst software (Applied Biosystems/MDS SCIEX, version 1.6.2).

Chromatographic separation was achieved on an Agilent Eclipse plus C18 column (100 mm × 2.1 mm, 3.5 μm; Agilent, USA) and maintained at 30 °C. The mobile phase consisted of methanol-0.1% ammonia in water (80:20, v/v) with fast isocratic elution at a flow rate of 0.4 mL min−1 and run time of 5 min. The sample volume injected was 5 µL and the temperature of auto sampler was set at 4 °C.

The mass spectrometer was run in electrospray ionization (ESI) mode using multiple reaction monitoring (MRM) to monitor the mass transitions. The MRM transitions were chosen to be m/z 360.1 → m/z 175.1 for pretomanid, m/z 124.1 → m/z 81.0 for pyrazinamide, m/z 172.1 → m/z 128.1 for IS. The declustering potential values set for pretomanid, pyrazinamide and IS were 65 V, 38 and 50 V, respectively. The collision energy values set for pretomanid, pyrazinamide and IS were 35 eV, 26 and 19 eV. The electrospray ionization voltage in positive mode was set 3,500 V. The turbo spray temperature was maintained at 350 °C. The curtain gas, gas 1 (nebulizer gas), and gas 2 (turbo gas, nitrogen) were 15, 50 and 50 psi, respectively. The product ion mass spectra of [M+H]+ of pretomanid, pyrazinamide and IS were presented in Fig. 1.

Fig. 1.
Fig. 1.

Product ion spectra of [M + H]+ of pretomanid (A), pyrazinamide (B), metronidazole (IS) (C) and their fragmentation pathways

Citation: Acta Chromatographica 2022; 10.1556/1326.2022.01087

2.6 Method validation

The LC-MS/MS method was validated according to the US Food and Drug Administration guidelines on bioanalytical method validation (US Food and Drug Administration, 2001).

2.6.1 Specificity

The selectivity of the method was evaluated by analyzing six individual sources of blank plasma samples to ensure that there were no interfering peaks at the retention time of either pretomanid, pyrazinamide and IS.

2.6.2 Linearity and sensitivity

The standard calibration curve for spiked plasma samples containing pretomanid and pyrazinamide was linear over the range 50–7,500 ng mL−1 and 500–75,000 ng mL−1. The calibration curves for all plasma samples showed good linearity (r2 > 0.9967 for pretomanid, r2 > 0.9956 for pyrazinamide) over the concentration ranges tested. The LLOQ was 50 ng mL−1 (pretomanid) and 500 ng mL−1 (pyrazinamide), which was sensitive enough for the pharmacokinetic study of pretomanid and pyrazinamide for oral administration in rats.

2.6.3 Accuracy and precision

The precision and accuracy of the method were assessed by analyzing QC samples in six replicates at three QC levels on three validation days. The intra-day and inter-day precisions were calculated using one-way analysis of variance (ANOVA) in terms of RSD and they should not exceed 15%. The accuracy was calculated as percentage deviation of the measured concentration from the nominal concentration (often expressed as relative error, RE) and it should be within ±15%.

2.6.4 Stability

The stability of pretomanid (100, 1,000, 5,000 ng mL−1) and pyrazinamide (1,000, 8,000, 50,000 ng mL−1) in rat plasma was evaluated by six replicates at three different concentrations. The short-term stability was examined by keeping the replicates of samples at room temperature for 12 h. The long-term stability was assessed by carrying out the experiment after 45 days of storage at −20°C. Freeze-thaw stability was assessed over three freeze-thaw cycles. Post-preparation stability was assessed by analyzing the extracted samples kept in the autosampler at 4°C for 24 h.

2.6.5 Extraction recovery and matrix effect

The extraction recovery of pretomanid, pyrazinamide and IS from rat plasma were evaluated by comparing the response of the extracted (pre-spiked) QC samples with those of the blank plasma at an equivalent concentration. The extraction recovery of pretomanid and pyrazinamide was determined at three different concentrations (high, medium, low), while IS at a single concentration of 50 ng mL−1. The recovery was expressed by the mean ± standard deviation (mean ± SD). The matrix effect was evaluated by comparing the response of the spike-after-extraction with those of neat samples at an equivalent concentration. The matrix effect was determined at three different concentrations (high, medium, low) and expressed by mean ± SD. The assessment of a relative matrix effect was performed based on direct comparison of the responses (peak areas) of the analyte spiked into extracts originating from six different lots (sources) of biofluids. The variability in these responses, determined as RSD (%), was considered as measure of relative matrix effect for a given analyte.

2.7 Pharmacokinetic application

All data were subsequently processed by the Analyst software (Applied Biosystems/MDS SCIEX, version 1.6.2) and Statistics version 3.0 (DAS 3.0, Anhui Provincial Center for Drug Clinical Evaluation). Data were shown as mean ± standard deviation (mean ± SD). The difference between groups was analyzed using student's t-test. A P-value less than 0.05 was considered as statistically significant.

3 Results and discussion

3.1 Method validation

3.1.1 Specificity

The selectivity of the method was assessed by LC-MS/MS derived from blank plasma samples. Figure 2 shows the typical chromatograms of a blank plasma sample, a blank plasma sample spiked with pretomanid, pyrazinamide and IS, a plasma sample from a rat 1 h after an oral administration. Under the given condition, pretomanid, pyrazinamide and IS eluted at retention time of 4.08 min, 3.64 min and 3.60 min. The result demonstrated that there was no interference with the determination of the pretomanid, pyrazinamide and IS, granting good method selectivity.

Fig. 2.
Fig. 2.

Representative MRM chromatograms for pretomanid, pyrazinamide and IS: (A) a blank plasma sample; (B) a blank plasma sample spiked with pretomanid (20 ng mL−1), pyrazinamide (150 ng mL−1) and IS (50 ng mL−1); (C) a plasma sample from a healthy rat 1h after an oral administration of pretomanid (20 mg kg−1) and pyrazinamide (150 mg kg−1)

Citation: Acta Chromatographica 2022; 10.1556/1326.2022.01087

3.1.2 Linearity and sensitivity

The calibration curves were obtained over the concentration range 50–7,500 ng mL−1 for pretomanid and 500–75,000 ng mL−1 for pyrazinamide in plasma in all biosamples with a correlation coefficient (y = 0.642x + 0.024, r2 > 0.9967 for pretomanid, y = 0.046x + 0.011, r2 > 0.9956 for pyrazinamide). The lowest limit of quantification (LLOQ) was defined as the lower concentration could be determined with both accurately and precisely.

3.1.3 Accuracy and precision

The accuracy and precision were estimated by RE and RSD. The results of intra- day and inter-day precision and accuracy for the assay of pretomanid and pyrazinamide in rat plasma were summarized in Table 1. The intra- day and inter-day RSD (%) were both no more than 9.87%, while the RE (%) of assay accuracies ranged from −6.12 to 11.63%. These results suggest that the method was reliable and reproducible for the quantitative pretomanid and pyrazinamide in rat plasma. The LLOQ for analytes at which both precision and accuracy were less than 20% and within ±20%, respectively.

Table 1.

Precision and accuracy for pretomanid and pyrazinamide in rat plasma (n = 6, Mean ± SD)

Spiked conc. (ng mL−1)Intra-day (n = 6)Inter-day (n = 3 × 6)
PrecisionAccuracyPrecisionAccuracy
(% RSD)(% RE)(% RSD)(% RE)
Pretomanid506.459.456.34−6.12
1007.127.145.368.34
1,0007.956.252.476.45
5,0006.27−5.636.977.12
Pyrazinamide5009.879.648.396.39
1,0003.967.694.958.42
8,0005.1211.636.873.24
50,0007.655.273.875.73

3.1.4 Stability

The data of stability which summarized in Table 2 indicated that pretomanid and pyrazinamide were stable in frozen for 45 days, three freeze–thaw cycles, room temperature for 12 h, prepared samples in Freezer (4°C) for 24 h. The results proved that the method for sample extraction, storage and intermittent analysis were validated and suited for large scale sample analysis.

Table 2.

Stability of pretomanid and pyrazinamide in rat plasma under different storage conditions (n = 6, Mean ± SD)

AnalytesSpiked conc. (ng mL−1)Post-preparation 12 h at room temperatureFrozen (−20 °C) for 45 daysThree freeze-thaw cyclesAuto-sampler stability at 4 °C for 24 h
Accuracy (%)Accuracy (%)Accuracy (%)Accuracy (%)
Pretomanid1006.348.956.468.45
1,0007.647.64−5.169.15
5,0003.942.967.91−7.11
Pyrazinamide1,0005.666.796.156.37
8,00010.94−9.157.157.89
50,000−8.743.574.884.48

3.1.5 Extraction recovery and matrix effect

The extraction recoveries of pretomanid, pyrazinamide and IS shown in Table 3. It was proved that the method was consistent, reproducible, and acceptable. The results of matrix effects of pretomanid, pyrazinamide and IS were summarized in Table 3. It was indicated that the method was acceptable in different matrix.

Table 3.

Recovery and matrix effect of pretomanid and pyrazinamide in rat plasma (n = 6, Mean ± SD)

AnalytesSpiked conc.RecoveryMatrix effect
(ng mL−1)(Mean ± SD %)RSD (%)(Mean ± SD %)RSD (%)
Pretomanid10097.42 ± 5.565.7193.38 ± 3.643.89
1,00095.83 ± 1.701.7895.21 ± 2.963.10
5,00096.15 ± 3.283.4297.26 ± 2.112.17
Pyrazinamide1,00093.93 ± 3.243.4696.37 ± 1.671.73
8,000103.46 ± 3.723.5998.05 ± 3.353.42
50,00096.79 ± 2.032.0997.67 ± 4.333.42
IS5091.52 ± 5.496.0591.76 ± 8.729.50

3.2 Optimization of LC–MS/MS conditions

It was a challenge to establish a suitable biological analysis method for simultaneous determination of pretomanid and pyrazinamide in plasma. After reviewing the literature [17–19], we decided to use LC-MS/MS to complete the simultaneous determination of the two drugs. Both positive and negative ion modes were used in our attempts to optimize the LC-MS response to pretomanid and pyrazinamide. Detection in positive ion mode was chosen due to stronger and more sensitive responses for both drugs and IS. The MRM transitions were chosen to be m/z 360.1 → m/z 175.1 for pretomanid, m/z 124.1 → m/z 81.0 for pyrazinamide, m/z 172.1 → m/z 128.1 for IS. Initially, we chose an Inertsil ODS3 C18 column to complete the separation, but the experimental results were always unsatisfactory because of the poor peak shape of metformin. Subsequently, good peak shape and successful separation were achieved on an Agilent Eclipse plus C18 column. The best resolution in terms of peak shape and strong signal was obtained using mobile phase A was methanol (A) and mobile phase B was 0.1% ammonia in water. A flow rate of 0.4 mL min−1 and operation time of 5.0 min were used for isocratic elution (A: B = 80:20, v/v).

3.3 Pharmacokinetic application

In the present study, the LC–MS/MS method was applied to the determination of pretomanid, pyrazinamide, and their combination in rat plasma, then we investigate and compared the pharmacokinetic parameters of rats which were administered pretomanid, pyrazinamide and pretomanid plus pyrazinamide, respectively. The main pharmacokinetic parameters calculated using non-compartmental analysis were shown in Table 4. Mean plasma concentration–time curves (n = 8) were presented in Figs 3 and 4. For pretomanid, there were little changes in the main pharmacokinetic parameters of pretomanid between alone and combined groups. Meanwhile, significant differences of AUC(0–t), tmax and t1/2 of pyrazinamide were observed between the alone and combined groups after administration to rats. The AUC(0–t), t1/2, tmax of pyrazinamide were decreased when the drug was co-administered with pretomanid, but the Cmax of pyrazinamide almost no change at all. The results show that there is an obvious pharmacokinetic interaction between pretomanid and pyrazinamide, which is manifested in the changes of the pharmacokinetic parameters of pyrazinamide.

Table 4.

Main pharmacokinetic parameters of pretomanid and pyrazinamide after oral administration of pretomanid (20 mg kg−1) and pyrazinamide (150 mg kg−1) alone and their combination in SD rats (n = 8, Mean ± SD)

ParameterPretomanidPyrazinamide
PretomanidPretomanid + PyrazinamidePyrazinamidePretomanid + Pyrazinamide
AUC(0-t) (ng mL−1·min−1)3401550.2 ± 354614.33527401.5 ± 1129228.532302911.5 ± 2502411.626919693.1 ± 2460902.1
AUC(0-∞) (ng mL−1·min−1)3661748.5 ± 332917.73933291.7 ± 1463467.838707718.5 ± 4465558.329172451.1 ± 3191819.7
tmax (min)360 ± 64.1375 ± 76.9210 ± 64.1153.7 ± 54.2
t1/2 (min)499.8 ± 155.4556.2 ± 163.2803.5 ± 215.7581.8 ± 196.6
CLz/F (L min−1 kg−1)0.006 ± 0.0010.006 ± 0.0010.004 ± 0.0010.005
Cmax (ng mL−1)3753.7 ± 729.23542.8 ± 799.833962.8 ± 3063.535750.3 ± 3224.7
Fig. 3.
Fig. 3.

Mean plasma concentration–time profiles (n = 8, Mean ± SD) of pretomanid (20 mg mL−1) alone and pretomanid (20 mg mL−1) plus pyrazinamide (150 mg kg−1) after oral administration to rats

Citation: Acta Chromatographica 2022; 10.1556/1326.2022.01087

Fig. 4.
Fig. 4.

Mean plasma concentration–time profiles (n = 8, Mean ± SD) of pyrazinamide (150 mg kg−1) alone and pretomanid (20 mg mL−1) plus pyrazinamide (150 mg kg−1) after oral administration to rats

Citation: Acta Chromatographica 2022; 10.1556/1326.2022.01087

4 Conclusion

In summary, a simple, sensitive and accurate LC-MS/MS method was developed and validated for the simultaneous determination of pretomanid and pyrazinamide in rat plasma, and it was applied to investigate the pharmacokinetics of these two drugs in rats. The drug-drug interaction of pretomanid and pyrazinamide in rats was reported for the first time. We studied the differences in the pharmacokinetic parameters of the two drugs used alone and in combination to investigate whether there is drug-drug interaction between the two drugs. Significant changes in AUC(0–t), tmax and t1/2 of pyrazinamide occurred after the two drugs were given at the same time. The pharmacokinetic drug-drug interaction results indicated that the pharmacokinetic parameters of pyrazinamide would affected by combined medication. It is hoped that our work would provide some reliable evidence for the safety of clinical medications.

Acknowledgment

This research was supported by the Basic Research plan of Natural Science of Shaanxi Province, China (Grant No: 2021JQ-887) and Scientific Research Program Funded by Education Department of Shaanxi Provincial Government (Grant No: 21JK0578).

References

  • 1.

    Kharwadkar, S.; Attanayake, V.; Duncan, J.; Navaratne, N.; Benson, J. The impact of climate change on the risk factors for tuberculosis: a systematic review. Environ. Res. 2022, 212, 113436.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Feng, Q.; Hu, X.; Zhao, J.; Huang, J.; Liu, L. Female genital tuberculosis presented with primary infertility and persistent CA-125 elevation: a case report. Ann. Med. Surg. 2022, 78, 103683.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Stewart, G. R.; Robertson, B. D.; Young, D. B. Tuberculosis: a problem with persistence. Nat. Rev. Microbiol. 2003, 1, 97105.

  • 4.

    Nachega, J. B.; Chaisson, R. E. Tuberculosis drug resistance: a global threat. Clin. Infect. Dis. 2003, 36, S2430.

  • 5.

    Sun, J.; Champion, P. A.; Bigi, F. Editorial: cellular and molecular echanisms of Mycobacterium tuberculosis virulence. Front. Cell Infect. Microbiol. 2019, 9.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Cole, S. T. Mechanisms of drug resistance in Mycobacterium tuberculosis. Front Biosci. 2009, 191, 975994.

  • 7.

    WHO Global tuberculosis report, 2019. https://apps.who.int/iris/bitstream/handle/10665/329368/9789241565714-eng.pdf? ua=1.

  • 8.

    Haydel, S. E. Extensively drug-resistant tuberculosis: a sign of the times and an impetus for antimicrobial discovery. Pharmaceuticals 2010, 3, 22682290.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Prasad, R. Multidrug and extensively drug-resistant TB (M/XDR-TB): problems and solutions. Indian J. Tuberc. 2010, 57, 180191.

  • 10.

    Stancil, S. L.; Mirzayev, F.; Abdel-Rahman, S. M. Profiling pretomanid as a therapeutic option for TB infection: evidence to date. Drug Des. Develop. Ther. 2021, 15, 28152830.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Bahuguna, A.; Rawat, D. S. An overview of new antitubercular drugs, drug candidates, and their targets. Med. Res. Rev. 2020, 40, 263292.

  • 12.

    Kadura, S.; King, N.; Nakhoul, M.; Zhu, H.; Theron, G.; Köser, C. U.; Farhat, M. Systematic review of mutations associated with resistance to the new and repurposed Mycobacterium tuberculosis drugs bedaquiline, clofazimine, linezolid, delamanid and pretomanid. J. Antimicrob. Chemother. 2020, 75, 20312043.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Stehr, M.; Elamin, A.; Singh, M. Pyrazinamide: the importance of uncovering the mechanisms of action in mycobacteria: expert Review of Anti-infective Therapy. Expert Rev. Anti-infective Ther. 2015, 13(5).

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Njire, M.; Tan, Y.; Mugweru, J.; Wang, C.; Guo, J.; Yew, W.; Tan, S.; Zhang, T. Pyrazinamide resistance in Mycobacterium tuberculosis: review and update. Adv. Med. Sci. 2016, 61, 6371.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Younossian, A. B.; Rochat, T.; Ketterer, J.-P.; Wacker, J.; Janssens, J.-P. High hepatotoxicity of pyrazinamide and ethambutol for treatment of latent tuberculosis. Eur. Respir. J. 2005, 26, 462464.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    Diacon, A. H.; Dawson, R.; Groote-Bidlingmaier, F. V.; Symons, G.; Venter, A.; Donald, P. R.; Niekerk, C. V.; Everitt, D.; Hutchings, J.; Burger, D. A. Bactericidal activity of pyrazinamide and clofazimine alone and in combinations with pretomanid and bedaquiline. Am. J. Respir. Crit. Care Med. 2015, 191, 943.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17.

    Wang, L.; Xu, Y.; Liang, L.; Diao, C.; Liu, X.; Zhang, J.; Zhang, S. LC-MS/MS method for the simultaneous determination of PA-824, moxifloxacin and pyrazinamide in rat plasma and its application to pharmacokinetic study. J. Pharm. Biomed. Anal. 2014, 97, 18.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18.

    Bratkowska, D.; Shobo, A.; Singh, S.; Bester, L.A.; Kruger, H. G.; Maguire, G.; Govender, T. Determination of the antitubercular drug PA-824 in rat plasma, lung and brain tissues by liquid chromatography tandem mass spectrometry: application to a pharmacokinetic study. J. Chromatogr. B 2015, 988, 187194.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19.

    Sanyal, M.; Shrivastav, S. P.; Shah, V. J.; Sharma, P.; Priyanka, A. An improved LC-MS/MS method for the simultaneous determination of pyrazinamide, pyrazinoic acid and 5-hydroxy pyrazinoic acid in human plasma for a pharmacokinetic study. J. Chromatogr. B. Anal. Tech. Biomed. Life Sci. 2016.

    • Search Google Scholar
    • Export Citation
  • 1.

    Kharwadkar, S.; Attanayake, V.; Duncan, J.; Navaratne, N.; Benson, J. The impact of climate change on the risk factors for tuberculosis: a systematic review. Environ. Res. 2022, 212, 113436.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Feng, Q.; Hu, X.; Zhao, J.; Huang, J.; Liu, L. Female genital tuberculosis presented with primary infertility and persistent CA-125 elevation: a case report. Ann. Med. Surg. 2022, 78, 103683.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Stewart, G. R.; Robertson, B. D.; Young, D. B. Tuberculosis: a problem with persistence. Nat. Rev. Microbiol. 2003, 1, 97105.

  • 4.

    Nachega, J. B.; Chaisson, R. E. Tuberculosis drug resistance: a global threat. Clin. Infect. Dis. 2003, 36, S2430.

  • 5.

    Sun, J.; Champion, P. A.; Bigi, F. Editorial: cellular and molecular echanisms of Mycobacterium tuberculosis virulence. Front. Cell Infect. Microbiol. 2019, 9.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Cole, S. T. Mechanisms of drug resistance in Mycobacterium tuberculosis. Front Biosci. 2009, 191, 975994.

  • 7.

    WHO Global tuberculosis report, 2019. https://apps.who.int/iris/bitstream/handle/10665/329368/9789241565714-eng.pdf? ua=1.

  • 8.

    Haydel, S. E. Extensively drug-resistant tuberculosis: a sign of the times and an impetus for antimicrobial discovery. Pharmaceuticals 2010, 3, 22682290.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Prasad, R. Multidrug and extensively drug-resistant TB (M/XDR-TB): problems and solutions. Indian J. Tuberc. 2010, 57, 180191.

  • 10.

    Stancil, S. L.; Mirzayev, F.; Abdel-Rahman, S. M. Profiling pretomanid as a therapeutic option for TB infection: evidence to date. Drug Des. Develop. Ther. 2021, 15, 28152830.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Bahuguna, A.; Rawat, D. S. An overview of new antitubercular drugs, drug candidates, and their targets. Med. Res. Rev. 2020, 40, 263292.

  • 12.

    Kadura, S.; King, N.; Nakhoul, M.; Zhu, H.; Theron, G.; Köser, C. U.; Farhat, M. Systematic review of mutations associated with resistance to the new and repurposed Mycobacterium tuberculosis drugs bedaquiline, clofazimine, linezolid, delamanid and pretomanid. J. Antimicrob. Chemother. 2020, 75, 20312043.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Stehr, M.; Elamin, A.; Singh, M. Pyrazinamide: the importance of uncovering the mechanisms of action in mycobacteria: expert Review of Anti-infective Therapy. Expert Rev. Anti-infective Ther. 2015, 13(5).

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Njire, M.; Tan, Y.; Mugweru, J.; Wang, C.; Guo, J.; Yew, W.; Tan, S.; Zhang, T. Pyrazinamide resistance in Mycobacterium tuberculosis: review and update. Adv. Med. Sci. 2016, 61, 6371.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Younossian, A. B.; Rochat, T.; Ketterer, J.-P.; Wacker, J.; Janssens, J.-P. High hepatotoxicity of pyrazinamide and ethambutol for treatment of latent tuberculosis. Eur. Respir. J. 2005, 26, 462464.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    Diacon, A. H.; Dawson, R.; Groote-Bidlingmaier, F. V.; Symons, G.; Venter, A.; Donald, P. R.; Niekerk, C. V.; Everitt, D.; Hutchings, J.; Burger, D. A. Bactericidal activity of pyrazinamide and clofazimine alone and in combinations with pretomanid and bedaquiline. Am. J. Respir. Crit. Care Med. 2015, 191, 943.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17.

    Wang, L.; Xu, Y.; Liang, L.; Diao, C.; Liu, X.; Zhang, J.; Zhang, S. LC-MS/MS method for the simultaneous determination of PA-824, moxifloxacin and pyrazinamide in rat plasma and its application to pharmacokinetic study. J. Pharm. Biomed. Anal. 2014, 97, 18.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18.

    Bratkowska, D.; Shobo, A.; Singh, S.; Bester, L.A.; Kruger, H. G.; Maguire, G.; Govender, T. Determination of the antitubercular drug PA-824 in rat plasma, lung and brain tissues by liquid chromatography tandem mass spectrometry: application to a pharmacokinetic study. J. Chromatogr. B 2015, 988, 187194.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19.

    Sanyal, M.; Shrivastav, S. P.; Shah, V. J.; Sharma, P.; Priyanka, A. An improved LC-MS/MS method for the simultaneous determination of pyrazinamide, pyrazinoic acid and 5-hydroxy pyrazinoic acid in human plasma for a pharmacokinetic study. J. Chromatogr. B. Anal. Tech. Biomed. Life Sci. 2016.

    • Search Google Scholar
    • Export Citation
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Senior editors

Editor(s)-in-Chief: Kowalska, Teresa

Editor(s)-in-Chief: Sajewicz, Mieczyslaw

Editors(s)

  • Danica Agbaba (University of Belgrade, Belgrade, Serbia)
  • Ivana Stanimirova-Daszykowska (University of Silesia, Katowice, Poland)
  • Monika Waksmundzka-Hajnos (Medical University of Lublin, Lublin, Poland)

Editorial Board

  • R. Bhushan (The Indian Institute of Technology, Roorkee, India)
  • J. Bojarski (Jagiellonian University, Kraków, Poland)
  • B. Chankvetadze (State University of Tbilisi, Tbilisi, Georgia)
  • M. Daszykowski (University of Silesia, Katowice, Poland)
  • T.H. Dzido (Medical University of Lublin, Lublin, Poland)
  • A. Felinger (University of Pécs, Pécs, Hungary)
  • K. Glowniak (Medical University of Lublin, Lublin, Poland)
  • B. Glód (Siedlce University of Natural Sciences and Humanities, Siedlce, Poland)
  • A. Gumieniczek (Medical University of Lublin, Lublin, Poland)
  • U. Hubicka (Jagiellonian University, Kraków, Poland)
  • K. Kaczmarski (Rzeszow University of Technology, Rzeszów, Poland)
  • H. Kalász (Semmelweis University, Budapest, Hungary)
  • K. Karljiković Rajić (University of Belgrade, Belgrade, Serbia)
  • I. Klebovich (Semmelweis University, Budapest, Hungary)
  • A. Koch (Private Pharmacy, Hamburg, Germany)
  • Ł. Komsta (Medical University of Lublin, Lublin, Poland)
  • P. Kus (Univerity of Silesia, Katowice, Poland)
  • D. Mangelings (Free University of Brussels, Brussels, Belgium)
  • E. Mincsovics (Corvinus University of Budapest, Budapest, Hungary)
  • Á. M. Móricz (Centre for Agricultural Research, Budapest, Hungary)
  • G. Morlock (Giessen University, Giessen, Germany)
  • A. Petruczynik (Medical University of Lublin, Lublin, Poland)
  • R. Skibiński (Medical University of Lublin, Lublin, Poland)
  • B. Spangenberg (Offenburg University of Applied Sciences, Germany)
  • T. Tuzimski (Medical University of Lublin, Lublin, Poland)
  • Y. Vander Heyden (Free University of Brussels, Brussels, Belgium)
  • A. Voelkel (Poznań University of Technology, Poznań, Poland)
  • B. Walczak (University of Silesia, Katowice, Poland)
  • W. Wasiak (Adam Mickiewicz University, Poznań, Poland)
  • I.G. Zenkevich (St. Petersburg State University, St. Petersburg, Russian Federation)

 

KOWALSKA, TERESA
E-mail: kowalska@us.edu.pl

SAJEWICZ, MIECZYSLAW
E-mail:msajewic@us.edu.pl

Indexing and Abstracting Services:

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2021  
Web of Science  
Total Cites
WoS
652
Journal Impact Factor 2,011
Rank by Impact Factor Chemistry, Analytical 66/87
Impact Factor
without
Journal Self Cites
1,789
5 Year
Impact Factor
1,350
Journal Citation Indicator 0,40
Rank by Journal Citation Indicator Chemistry, Analytical 72/99
Scimago  
Scimago
H-index
29
Scimago
Journal Rank
0,27
Scimago Quartile Score Chemistry (miscellaneous) (Q3)
Scopus  
Scopus
Cite Score
2,8
Scopus
CIte Score Rank
General Chemistry 210/409 (Q3)
Scopus
SNIP
0,586

2020
 
Total Cites
650
WoS
Journal
Impact Factor
1,639
Rank by
Chemistry, Analytical 71/83 (Q4)
Impact Factor
 
Impact Factor
1,412
without
Journal Self Cites
5 Year
1,301
Impact Factor
Journal
0,34
Citation Indicator
 
Rank by Journal
Chemistry, Analytical 75/93 (Q4)
Citation Indicator
 
Citable
45
Items
Total
43
Articles
Total
2
Reviews
Scimago
28
H-index
Scimago
0,316
Journal Rank
Scimago
Chemistry (miscellaneous) Q3
Quartile Score
 
Scopus
393/181=2,2
Scite Score
 
Scopus
General Chemistry 215/398 (Q3)
Scite Score Rank
 
Scopus
0,560
SNIP
 
Days from
58
submission
 
to acceptance
 
Days from
68
acceptance
 
to publication
 
Acceptance
51%
Rate

2019  
Total Cites
WoS
495
Impact Factor 1,418
Impact Factor
without
Journal Self Cites
1,374
5 Year
Impact Factor
0,936
Immediacy
Index
0,460
Citable
Items
50
Total
Articles
50
Total
Reviews
0
Cited
Half-Life
6,2
Citing
Half-Life
8,3
Eigenfactor
Score
0,00048
Article Influence
Score
0,164
% Articles
in
Citable Items
100,00
Normalized
Eigenfactor
0,05895
Average
IF
Percentile
20,349
Scimago
H-index
26
Scimago
Journal Rank
0,255
Scopus
Scite Score
226/167=1,4
Scopus
Scite Score Rank
Chemistry (miscellaneous) 240/398 (Q3)
Scopus
SNIP
0,494
Acceptance
Rate
41%

 

Acta Chromatographica
Publication Model Online only
Gold Open Access
Submission Fee none
Article Processing Charge 400 EUR/article
Regional discounts on country of the funding agency World Bank Lower-middle-income economies: 50%
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Acta Chromatographica
Language English
Size A4
Year of
Foundation
1992
Volumes
per Year
1
Issues
per Year
4
Founder Institute of Chemistry, University of Silesia
Founder's
Address
PL-40-007 Katowice, Poland, Bankowa 12
Publisher Akadémiai Kiadó
Publisher's
Address
H-1117 Budapest, Hungary 1516 Budapest, PO Box 245.
Responsible
Publisher
Chief Executive Officer, Akadémiai Kiadó
ISSN 2083-5736 (Online)

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