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  3. In-vitro metabolism, CYP profiling and metabolite identification of E- and Z- guggulsterone, a potent hypolipidmic agent

In-vitro metabolism, CYP profiling and metabolite identification of E- and Z- guggulsterone, a potent hypolipidmic agent

  • J Pharm Biomed Anal. 2018 Oct 25:160:202-211. doi: 10.1016/j.jpba.2018.06.047.
Yashpal S Chhonker 1,  Hardik Chandasana 2,  Veenu Bala 3,  Rao Mukkavilli 4,  Deepak Kumar 5,  Subrahmanyam Vangala 6,  Rabi S Bhatta 7
Affiliations

Affiliations

  • 1 Pharmacokinetics & Metabolism Div., CSIR- Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, Rafi Marg, New Delhi, 110 001, India; College of Pharmacy, Department of Pharmacy Practice, University of Nebraska Medical Centre, Omaha, NE, USA.
  • 2 Pharmacokinetics & Metabolism Div., CSIR- Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, Rafi Marg, New Delhi, 110 001, India; Department of Pharmaceutics, University of Florida, FL, USA.
  • 3 Medicinal & Process Chemistry Div., CSIR- Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, Rafi Marg, New Delhi, 110 001, India; Department of Pharmaceutical Sciences, Mohanlal Sukhadia University, Udaipur, India.
  • 4 Advinus Therapeutics Limited, Bengaluru, Karnataka, India; Georgia State University, Atlanta, USA.
  • 5 Pharmacokinetics & Metabolism Div., CSIR- Central Drug Research Institute, Lucknow, 226031, India.
  • 6 Advinus Therapeutics Limited, Bengaluru, Karnataka, India; Incan Solutions Private Limited, Nova Scotia, Canada.
  • 7 Pharmacokinetics & Metabolism Div., CSIR- Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, Rafi Marg, New Delhi, 110 001, India. Electronic address: rabi_bhatta@cdri.res.in.
PMID: 30099292 DOI: 10.1016/j.jpba.2018.06.047
Abstract

The polyphenol E- and Z-gugggulsterone (GS) is an antagonist ligand for the Farnesoid X Receptor (FXR) and known to possess potent hypolipidemic properties as shown in various preclinical and clinical studies. In the present study, we examined drug-like properties of GS by assessing the isomers plasma protein binding, metabolic stability, CYP profiling, CYP inhibition, and phase I and II metabolite identification of GS using liver microsomes and S9 fractions. GS followed Lipinski and Veber rules and were substrates of CYP3A CYP2C19 and CYP2D6 isoforms. GS was also found to be an inhibitor of CYP2C19 with an IC50 value of 2.1 μM. GS showed high plasma protein binding (<96%), and low to moderate binding with human serum albumin (∼70%). Unbound intrinsic clearances (CLint, in-vitro) was determined to be low at 0.029 ± 0.0009 and 0.027 ± 0.008 mL/min/mg protein for E- and Z-isomer, respectively in human liver microsomes. Nineteen phase I and II metabolites were identified and hydroxylation was found to be major metabolic pathway using human liver microsomes and S9 fractions. The results of in-vitro drug-metabolism studies provide impetus for further structural modification of this pharmacophore in order to improve the stability of drugs with potent hypolipidemic effects.

Keywords

CYP inhibition; CYP phenotyping; Guggulsterone; LC–MS/MS; metabolic stability.

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