Stereoselective pharmacokinetics and tissue distribution of levodropropizine after administration of pure levodropropizine and the <i>rac</i>-dropropizine to Sprague–Dawley rats

Gabani, Bhavesh Babulal; Todmal, Umesh; Saini, Neeraj Kumar; Balakrishna, Vinod Anera; Sulochana, Suresh P.; Timmapuram, Ashok; Zainuddin, Mohd; Balaji, Narayanan; Praharaj, Shuvranshu; Srinivas, Nuggehally R.; Mullangi, Ramesh

doi:10.1080/00498254.2019.1599148

Cited by 3 publications

(1 citation statement)

References 9 publications

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“…The AUC 0-∞ (area under curve from time zero to infinity) was found to be 26.4 µg × h/mL with a terminal half-life (t½) of 6.01 h. On other hand, AGI-16903 attained T max at 8.0 h. The AUC 0-∞ and t½ for AGI-16903 were 227 ng × h/mL and 12.4 h, respectively. In order to investigate the huge difference in AUC 0-∞ and C max between enasidenib and AGI-16903, we have determined the metabolic stability in mice and human liver microsomes using the procedure reported by Gabani et al [15]. The % remained was 94.7 and 74.4 in mice liver microsomes and 97.6 and 80.7 in human liver microsomes, for enasidenib and AGI-16903, respectively at the end of 30 min incubation time.…”

Section: Pharmacokinetic Studymentioning

confidence: 99%

Validated LC-MS/MS Method for Simultaneous Quantitation of Enasidenib and its Active Metabolite, AGI-16903 in Small Volume Mice Plasma: Application to a Pharmacokinetic Study

et al. 2019

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Enasidenib is a selective mutant isocitrate dehydrogenase 2 inhibitor approved for the treatment of relapsed and refractory acute myeloid leukemia patients. A sensitive and rapid method has been developed and validated as per regulatory guideline for the simultaneous quantitation of enasidenib and its active metabolite, AGI-16903 in mice plasma using an LC-MS/MS. Enasidenib and AGI-16903 along with internal standard were extracted from mice plasma using simple protein precipitation method. Chromatographic resolution of enasidenib, AGI-16903 and the internal standard (close analogue of AGI-16903) was achieved on a Chromolith RP-18e column using 0.2% formic acid:acetonitrile (15:85, v/v) as an eluent, which was delivered at a flow-rate of 1.2 mL/min. The MS/MS ion transitions monitored were m/z 474.1→267.2, 402.1→188.1 and 421.0→146.1 for enasidenib, AGI-16903 and the internal standard, respectively. The linearity range was 1.01–3023 ng/mL for both enasidenib and AGI-16903. The within-run and between-run accuracy and within-run and between-run precision were in the range of − 2.29 to 2.72 (as one value is in negative side). and 4.65–9.82%, respectively for enasidenib; 0.19–10.3 and 3.22–9.22%, respectively for AGI-16903. Both enasidenib and AGI-16903 were found to be stable in stability (up to three freeze-thaw cycles and for long-term at −80°C for 30 days) and processed (bench-top for 6 h and in in-injector for 24 h) samples. Application of the validated method was shown in a pharmacokinetic study in mice.

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Section: Pharmacokinetic Studymentioning

confidence: 99%

Validated LC-MS/MS Method for Simultaneous Quantitation of Enasidenib and its Active Metabolite, AGI-16903 in Small Volume Mice Plasma: Application to a Pharmacokinetic Study

et al. 2019

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Characteristics, Properties and Analytical Methods for Determination of Dropropizine and Levodropropizine: A Review

Machado

Nemitz

Todeschini

et al. 2019

Critical Reviews in Analytical Chemistry

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Pharmacokinetics of Darolutamide in Mouse - Assessment of the Disposition of the Diastereomers, Key Active Metabolite and Interconversion Phenomenon: Implications to Cancer Patients

Saini

Gabani

Todmal

et al. 2021

DML

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Background: Darolutamide is recently approved for the treatment of non-metastatic castrate resistance prostate cancer. Hitherto, no stereoselective pharmacokinetic data has been published pertaining to darolutamide and its diastereomers in animals or humans. The key aims of the experiment were to examine darolutamide, S,S-darolutamide and S,R-darolutamide with respect to (a) assessment of in vitro stability and protein binding (b) characterization of in vivo oral and intravenous pharmacokinetics in mice. Method: In vitro (liver microsomes stability and protein binding) and in vivo experiments (oral/intravenous dosing to mice) were carried out using darolutamide, S,S-darolutamide and S,R-darolutamide. Besides, tissue levels of darolutamide, S,S-darolutamide and S,R-darolutamide were measured following oral and intravenous dosing. Appropriate plasma/tissue samples served to determine the pharmacokinetics of various analytes in mice. Liquid chromatography in tandem with mass spectrometry procedures enabled the delineation of the plasma pharmacokinetics, in vitro and tissue uptake data of the various analytes. Results: Chiral inversion was absent in the metabolic stability study. However, darolutamide showed profound stereoselectivity (S,Sdarolutamide greater than S,R-darolutamide) after either intravenous or oral dosing. S,R-darolutamide but not S,S-darolutamide showed conversion to its antipode post oral and intravenous dosing to mice. Regardless of oral or intravenous dosing, active keto darolutamide formation was evident after administration of darolutamide, S,S-darolutamide or S,R- darolutamide. Tissue data supported the observations in plasma; however, tissue exposure of the various darolutamide, S,S-darolutamide and S,R-darolutamide were much lower as compared to plasma. Conclusion: In lieu of the human pharmacokinetic data, although the administration of diastereomeric darolutamide was justified, it is proposed to delineate the clinical pharmacokinetics of S,R-darolutamide and S,S-darolutamide relative to darolutamide in future clinical pharmacology studies.

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Stereoselective pharmacokinetics and tissue distribution of levodropropizine after administration of pure levodropropizine and the rac-dropropizine to Sprague–Dawley rats

Cited by 3 publications

References 9 publications

Validated LC-MS/MS Method for Simultaneous Quantitation of Enasidenib and its Active Metabolite, AGI-16903 in Small Volume Mice Plasma: Application to a Pharmacokinetic Study

Validated LC-MS/MS Method for Simultaneous Quantitation of Enasidenib and its Active Metabolite, AGI-16903 in Small Volume Mice Plasma: Application to a Pharmacokinetic Study

Characteristics, Properties and Analytical Methods for Determination of Dropropizine and Levodropropizine: A Review

Pharmacokinetics of Darolutamide in Mouse - Assessment of the Disposition of the Diastereomers, Key Active Metabolite and Interconversion Phenomenon: Implications to Cancer Patients

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