A high throughput approach for simultaneous estimation of multiple synthetic trioxane derivatives using sample pooling for pharmacokinetic studies

Singh, Rajendra; Singh, Shio Kumar; Gupta, R. C.

doi:10.1016/j.jpba.2004.09.038

Cited by 8 publications

(3 citation statements)

References 14 publications

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“…5 Therefore, the ability to rapidly generate the PK properties for a large number of compounds has become very important during lead optimization. Several approaches such as pooling of plasma samples, [6][7][8] truncating PK sample period collection, 9 cassette-accelerated rapid rat screen, 10 snapshot PK, 11 automation of extraction processes, and column switching [12][13][14] have been suggested to increase throughput.…”

Section: Introductionmentioning

confidence: 99%

Cassette Dosing for Pharmacokinetic Screening in Drug Discovery: Comparison of Clearance, Volume of Distribution, Half-Life, Mean Residence Time, and Oral Bioavailability Obtained by Cassette and Discrete Dosing in Rats

Nagilla

Nord

McAtee

et al. 2011

Journal of Pharmaceutical Sciences

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Section: Introductionmentioning

confidence: 99%

Cassette Dosing for Pharmacokinetic Screening in Drug Discovery: Comparison of Clearance, Volume of Distribution, Half-Life, Mean Residence Time, and Oral Bioavailability Obtained by Cassette and Discrete Dosing in Rats

Nagilla

Nord

McAtee

et al. 2011

Journal of Pharmaceutical Sciences

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“…Chromatographic separations were achieved at a flow rate of 1.5 mL/min on a Spheri‐5 ODS Perkin Elmer Brownlee Column (5 µm, 220 × 4.6 mm) with a run time of 15 min. The wavelength was set at 247 nm and the injection volume was 50 μL (Singh et al , ).…”

Section: Methodsmentioning

confidence: 99%

Determination of metabolic profile of anti‐malarial trioxane CDRI 99/411 in rat liver microsomes using HPLC

Mishra

Manickavasagam

Jain

2011

Biomedical Chromatography

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CDRI 99/411 is a potent 1,2,4-trioxane anti-malarial candidate compound of the Central Drug Research Institute, India. This study aimed to conduct comprehensive in vitro metabolic investigations of CDRI 99/411 to corroborate its preclinical investigations. Preliminary in vitro metabolic investigations were performed to assess the metabolic stability [in vitro half-life (t(1/2) ) and in vitro hepatic intrinsic clearance (Cl(int) )] of CDRI 99/411 in male Sprague-Dawley rat and human liver microsomes using validated high-performance liquid chromatography with photodiode array detector. The observed in vitro t(1/2) of the compound in rat and human liver microsomes was 13 min with in vitro Cl(int) 130.7±25.0 μL/min/mg and 19 min with in vitro Cl(int) 89.3 ± 17.40 μL/min/mg. These observations suggested moderate metabolic degradation and in vitro Cl(int) with insignificant difference (p>0.05) in the metabolic stability profile in rat and human. Hence, in vitro metabolic investigations were performed with rat liver microsomes. It was observed that CDRI 99/411 exhibited sigmoidal kinetics. At nonlinear regression (r ≥ 0.99) EC(50) and Hill slope values were 17 µm and 1.50, respectively. The metabolism of CDRI 99/411 was primarily mediated by CYP3A2 and was inferred by CYP reaction phenotyping with known potent inhibitors. Two metabolites of CDRI 99/411 were detected which were undetectable on incubation with 1-aminobenzotriazole and ketoconazole.

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“…CDRI 99/411 ( Fig. 1 ) is a potent orally active 1,2,4-trioxane antimalarial candidate compound for the treatment of malaria [7] , [8] . 1,2,4-Trioxane ring system in artemisinin is essential for the antimalarial activity due to the presence of peroxide group [9] .…”

Section: Introductionmentioning

confidence: 99%

Assay method for quality control and stability studies of a new antimalarial agent (CDRI 99/411)

Khandelwal

Pachauri

Zaidi

et al. 2013

Journal of Pharmaceutical Analysis

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CDRI compound no. 99/411 is a potent 1,2,4-trioxane antimalarial candidate drug under development at our Institute. An HPLC method for determination of CDRI 99/411 with its starting material and intermediates has been developed and validated for in process quality control and stability studies. The analytical performance parameters such as linearity, precision, accuracy, specificity, limit of detection (LOD) and lower limit of quantification (LLOQ) were determined according to International Conference on Harmonization ICH Q2(R1) guidelines. HPLC separation was achieved on a RP-select B Lichrosphere® column (250 mm×4 mm, 5 μm, Merck) using water containing 0.1% glacial acetic acid and acetonitrile as the mobile phase in a gradient elution. The eluents were monitored by a photo diode array detector at 245 and 275 nm. Based on signal to noise ratio of 3 and 10 the LOD of CDRI 99/411 was 0.55 µg/mL, while the LLOQ was 1.05 µg/mL. The calibration curves were linear in the range of 1.05–68 µg/mL. Precision of the method was determined by inter- and intra-assay variations within the acceptable range.

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A high throughput approach for simultaneous estimation of multiple synthetic trioxane derivatives using sample pooling for pharmacokinetic studies

Cited by 8 publications

References 14 publications

Cassette Dosing for Pharmacokinetic Screening in Drug Discovery: Comparison of Clearance, Volume of Distribution, Half-Life, Mean Residence Time, and Oral Bioavailability Obtained by Cassette and Discrete Dosing in Rats

Cassette Dosing for Pharmacokinetic Screening in Drug Discovery: Comparison of Clearance, Volume of Distribution, Half-Life, Mean Residence Time, and Oral Bioavailability Obtained by Cassette and Discrete Dosing in Rats

Determination of metabolic profile of anti‐malarial trioxane CDRI 99/411 in rat liver microsomes using HPLC

Assay method for quality control and stability studies of a new antimalarial agent (CDRI 99/411)

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