Publications by authors named "Ansar Ali Khan"

4 Publications

  • Page 1 of 1

Identification, isolation and characterization of dolutegravir forced degradation products and their cytotoxicity potential.

J Pharm Biomed Anal 2019 Sep 18;174:588-594. Epub 2019 Jun 18.

SMS Pharmaceuticals Ltd., R&D Center, Gagillapur, Hyderabad -500 043, India.

Dolutegravir was approved by USFDA, Canada and European regulatory authorities as antiretroviral medication. In this article, DLG forced degradation studies as per the International Council for Harmonization (ICH) prescribed stress conditions was conducted and the resulting degradants were fully characterized. DLG was stable in basic, thermal and photolytic stress conditions, whereas DLG was found to unstable in acidic and oxidative conditions. One degradant each from acid and peroxide treated solutions was resolved on LC-MS and labelled as DP-1 and DP-2 with RT 1.80 min and 1.41 min, respectively. DP-1 and DP-2 were isolated by preparative HPLC with C18 column using gradient elution method. Subsequently DP-1 and DP-2 peaks were subjected to HRMS for accurate mass. Molecular mass of DP-1 and DP-2 were m/z 420.1379 (positive mode) and m/z 214.0319 (negative mode), respectively. Further, DP-1 & DP-2 were subjected to NMR spectroscopic analysis (including 2D) for structural confirmation. DP-1 was identified as N-(2,4-difluorobenzyl)-9-hydroxy-2-(4-hydroxybutan-2-yl)-1,8-dioxo-2,8-dihydro-1H-pyrido[1,2-a]pyrazine-7-carboxamide and it is earlier reported by Gudisela et al. [19] as DLG process impurity. DP-2 was identified as 2-(2,4difluorobenzylamino)-2-oxoacetic acid which is novel DLG degradant and not reported earlier to the best of our knowledge. DLG along its forced degradation products were found to be non-cytotoxic in in vitro assay conditions using HepG2 cells.
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http://dx.doi.org/10.1016/j.jpba.2019.06.022DOI Listing
September 2019

Altered pharmacokinetics of rosiglitazone in a mouse model of non-alcoholic fatty liver disease.

Drug Metab Pers Ther 2016 09;31(3):165-71

Background: Severe forms of non-alcoholic fatty liver disease (NAFLD) adversely affect the liver physiology and hence the pharmacokinetics of drugs. Here, we investigated the effect of NAFLD on the pharmacokinetics of rosiglitazone, an insulin sensitizer used in the treatment of type 2 diabetes.

Methods: Male C57BL/6 mice were divided into two groups. The first group (n=14) was fed with normal chow feed and the second group (n=14) was fed with 60% high-fat diet (HFD) and 40% high fructose liquid (HFL) for 60 days to induce NAFLD. The development of NAFLD was confirmed by histopathology, liver triglyceride levels and biochemical estimations, and used for pharmacokinetic investigations. Rosiglitazone was administered orally at 30 mg/kg dose. At predetermined time points, blood was collected and rosiglitazone concentrations were determined using LC/MS/MS. Plasma concentrations were subjected to non-compartmental analysis using Phoenix WinNonlin (6.3), and the area under the plasma concentration-time curve (AUC) was calculated by the linear-up log-down method.

Results: HFD and HFL diet successfully induced NAFLD in mice. Rosiglitazone pharmacokinetics in NAFLD animals were altered significantly as compared to healthy mice. Rosiglitazone exposure increased significantly in NAFLD mice (2.5-fold higher AUC than healthy mice). The rosiglitazone oral clearance was significantly lower and the mean plasma half-life was significantly longer in NAFLD mice as compared to healthy mice.

Conclusions: The NAFLD mouse model showed profound effects on rosiglitazone pharmacokinetics. The magnitude of change in rosiglitazone pharmacokinetics is similar to that observed in humans with moderate to severe liver disease. The present animal model can be utilized to study the NAFLD-induced changes in the pharmacokinetics of different drugs.
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http://dx.doi.org/10.1515/dmpt-2016-0008DOI Listing
September 2016

Effect of ultraviolet B (302 nm) irradiation on viability, metabolic and detoxification functions of goat hepatocytes--in vitro study.

Mol Cell Biochem 2005 Sep;277(1-2):49-53

Owaisi Hospital and Research Centre, Deccan College of Medical Sciences, Kanchanbagh, Hyderabad, 500 058, India.

The object of the present study was to investigate the effect(s) of UV-B irradiation on the functional integrity, metabolic and detoxifying capacity of the isolated goat hepatocytes. Isolated goat hepatocytes were subjected to UV-B irradiation invitro for 0, 250, 500, 1250, 2500 and 7500 Joules/m2 which correspond to the irradiation time of 0, 1, 2, 5, 10 and 30 min. Cells were then analysed for Viability (Trypan blue exclusion test [TBE], 3-[4,5-dimethylthiozol-2yl]-2,5-diphenyltetrazolium bromide [MTT] assay, Membrane integrity (Lactate dehydrogenase [LDH] leakage, Lipid peroxidation) Detoxification (Ureagenesis, Cytochrome P450 activity [CYP450, Diazepam metabolism] and Glutathione-S-Transferase [GST] activity. The results show that there was no difference in functional, metabolic as well as detoxifying parameters of the hepatocytes when irradiated from 0-1250 Joules/m2, whereas a significant alteration was appreciable in the parameters such as LDH leakage, lipid peroxidation, and CYP450 activity when irradiated beyond 1250 Joules/m2. Our present findings suggest that the biologically compatible and feasible dose of UV-B irradiation for xenotransplantation appears to be 1250 Joules/m2.
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http://dx.doi.org/10.1007/s11010-005-4881-3DOI Listing
September 2005
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