PK-PD Toxicology Division

Overview

The primary focus of the Division is to generate pre-clinical data of lead molecules of the ongoing drug discovery program of the Institute/sponsored molecules in the area of Pharmacokinetics (ADME) and regulatory toxicology.

PK-PD, Toxicology and Formulation division under CSIR-Indian Institute of Integrative Medicine is having the requisite facilities to provide services in the following areas:

Pharmacokinetics study of new chemical entities/drugs (Non-GLP):

  • Pharmacokinetic profiling in rat and mice following oral, intravenous and intraperitoneal route.
  • Plasma protein binding study.
  • Metabolic stability study with mouse, rat and human liver microsomes.
  • Parallel artificial membrane permeability assay (PAMPA).
  • Tissue distribution study in mice and rat.
  • Drug- drug interaction study

Bioanalytical method development and validation study

Pharmacodynamics study in mice/rat (Non-GLP):

  • Analgesic activity
  • Antiinflammatory activity
  • Antipyretic activity
  • Antiulcer activity
  • Antiarrthritic activity

Toxicity study in mice and rat (Non-GLP):

  • Acute (14 day)
  • Sub-acute (28 day)
  • Sub-chronic (90 day)
  • Chronic (180 Day)

Genotoxicity study: Sperm abnormality study

Reproductive toxicity study

Developmental study

Evaluation of haematological and biochemical parameters for any animal study.

Safety pharmacology study in : 

  • Cardiovascular system (ECG, BP, Respiratory rate)
  • Central nervous system (Hot plate method, spontaneous motor activity, convulsion activity, pentobarbitone induced sleeping time, effect on body temperature).
  • Gastro-intestinal system (Charcoal meal test in mice, bile secretion in rats)

Physicochemical parameters determination :

  • Solubility
  • Log P
  • Log D
  • Pka

Preclinical formulation development for oral and intravenous administration Skin biology

Anti Wrinkle (photoaging) activity :

  • Cytotoxicity/Cytotoprotection
  • Collagen content
  • Matrix Metalloproteinase (MMPs)
  • TGF-β
  • Tissue inhibitors of Metalloproteinases (TIMPs)
  • Hyaluronidase inhibition (Enzymatic assay)
  • Intracellular ROS/Oxidative stress assays
  • Pro-inflammatory cytokines
  • Anti-oxidant activity

Melanogenesis process.

  • Tyrosinase inhibition assay (Enzymatic)
  • Tyrosinase inhibition assay (Cellular)
  • Melanin synthesis in melanocytes
  • Melanocyte proliferation

Skin Cancer Biology

  • In vitro anti-cancer screening studies of test substances
  • In vivo skin cancer models induced by UV –irradiation

Mechanistic Studies: Exploring the mechanism of action of test substances using state of art biochemical and molecular biology techniques.

In vitro skin cell culture models.

 

In vitro skin cell culture models established here used to study the aging process induced by Ultraviolet -irradiation. The cell models that are available with us are

  • Normal human foreskin fibroblasts
  • Murine/Human Melanoma cells
  • Human Keratinocyte (HaCaT) Cells
  • Primary Human Skin Fibroblasts
  • Primary Human Skin Keratinocytes
  • Primary Human Skin Melanocytes

Vision & Mission

Vision:

  • The primary focus is to provide support to the ongoing drug discovery program of the i institute in the areas of Pharmacokinetics, ADME and Toxicology and generate preclinical data.

Mission: 

    • Development of validated protocols for HPLC/LC-MS-MS in terms of recovery, precision, accuracy and reproducibility.
    • PK studies of new chemical entities.
    • Absorption (A), distribution (D), Metabolism (M), Elimination (E) and protein binding profile.
    • Safety pharmacology
    • Regulatory Toxicology

Competencies

  • Pre-formulation
  • Pharmacokinetics
  • Bioavailability/ Bioequivalence studies
  • ADME Studies
  • Phase I Studies
  • Preparation of Pre-clinical/ Phase I Dossiers
  • In vivo toxicology (as per OECD/Schedule Y guidelines)
  • Safety pharmacological studies (as per ICH guidelines)

Research Facilities

Name No.
HPLC 2
LC-MS/MS 2
Multimode ELISA reader 1
Multiscan spectrum ELISA reader 1
Automated biochemical analyzer 1
Automated haematology analyzer 1
Automated urine analyzer 1
Spectrofluorometer 1
Spectrofluorometer (Plate reader) 1
RT-PCR 1
Fluorescent microscope 1
Rectal thermometer for rodents 1
Passive avoidance cage for mouse 1
Water maze for mouse and rat 1
Radial arm maze for mouse and rat 1
Analgesiometer (Hot plate) 1
Convulsometer 1
Tail Flick apparatus 1
Volume differential meter 1
Analytical balance 3
pH meter 1
Refrigerated centrifuge 2
Solvent evaporation system 1
Water purification system 1
Deep freezer 2
Particle size analyzer 1
Lyophiliser 1
Ultrasonic Homogenizer 1
Optical microscope 1

 

People

Dr. Zabeer Ahmed
Sr. Principal Scientist
Head PK-PD Toxicology

 

Dr. P.N Gupta
Principal Scientist

Dr. Sheikh Tasduq Abdullah
Principal Scientist

Dr. Ajay Kumar
Principal Scientist

Dr. Utpal Nandi
Sr. Scientist

Bhavna Vij
Technical Officer

Mrs. Priya Wazir
Technical Officer

Ongoing Projects

  • MLP-6006: Pre-clinical (PK-PD, safety and toxicity profile) of new bioactive leads and development of new combination drugs for cancer/tuberculosis
  • MLP-110004: Development of zinc gluconate-Vitamin C formulation for immunity improvement of coronavirus disease (COVID-19)
  • MLP- 6012: Safety pharmacology, toxicology and IND enabling study
  • GAP -2166: Discovery of target based novel bioactive natural products from a high altitude plant Hippophae rhamnoides L. (seabuckthorn) and Grewia asiatica (phalsa) for achieving pharmacological and cosmetics effects against ultraviolet radiation induced skin damage (photo-aging/ carcinogenesis)
  • GAP-0162: Mechanistic insights in the coexisting pathogenesis of Ethanol and High Cholesterol/High Fat diet -induced End Stage Liver Disease

 

Publication

Authors Title Journal
A. Dogra, S. Bhatt, A. Magotra, A. Sharma, P. Kotwal, A. Gour, P. Wazir, G. Singh, U. Nandi* Intervention of curcumin on oral pharmacokinetics of daclatasvir in rat: A possible risk for long‐term use. Phytotherapy Research
A. Dogra, A. Gour, S. Bhatt, P. Sharma, A. Sharma, P. Kotwal, P. Wazir, P. Mishra, G. Singh, U. Nandi* Effect of rutin on pharmacokinetic modulation of diclofenac in rats. Xenobiotica
A.U. Nissar, L. Sharma, M.A. Mudasir, L.A. Nazir, S.A. Umar, P.R. Sharma, R.A. Vishwakarma, S.T. Abdullah* Chemical chaperone 4-phenyl butyric acid (4PBA) reduces hepatocellular lipid accumulation and lipotoxicity through induction of autophagy. Journal of Lipid Research.
S.T, Abdullah, A. Krishnan, T. Mounajjed, S. Hartono, A. McConico, T.  White, N. LeBrasseur, I. Lanza, S. Nair, G. Gores, M. Charlton. A longitudinal study of whole body, tissue and cellular physiology in a mouse model of fibrosing NASH with high fidelity to the human condition. American Journal of Physiology-Gastrointestinal and Liver Physiology
A. Wani, S.B. Al Rihani, A. Sharma, B. Weadick, R. Govindarajan, S.U. Khan, P.R. Sharma, A. Dogra, U. Nandi, C.N. Reddy, S.S. Bharate, G. Singh, S.B. Bharate, R.A. Vishwakarma, A. Kaddoumi,  A. Kumar* Crocetin promotes clearance of amyloid-β by inducing autophagy via the STK11/LKB1-mediated AMPK pathway.

 

  Autophagy
A. Wani, M. Gupta, M. Ahmad, A.M. Shah, A. Ul Ahsan, P.H. Qazi, F. Malik, G. Singh, P.R. Sharma, A. Kaddoumi, S.B. Bharate, R.A. Vishwakarma, A. Kumar* Alborixin clears amyloid-β by inducing autophagy through PTEN mediated inhibition of AKT pathway.

 

 Autophagy
A. Saneja, D. Nayak, M. Srinivas, A. Kumar, V. Khare, A. Katoch, A. Goswami, R.A. Vishwakarma, S.D. Sawant, P.N. Gupta* Development and mechanistic insight into enhanced cytotoxic potential of hyaluronic acid conjugated nanoparticles in CD44 overexpressing cancer cells. European Journal of Pharmaceutical Sciences, 2017, 97, 79-91.
R.D. Dubey, R. Klippstein, J. Wang, N. Hodgins, K. Mei, J. Sosabowski, R.C. Hider, V. Abbate, P.N. Gupta, K.T. Al-Jamal

 

 Novel hyaluronic acid conjugates for dual nuclear imaging and therapy in CD44-expressing tumors in mice in vivo.

 

 Nanotheranostics, 2017

Patents:

Inventors/ Contributors Title Description Year
A. Kumar, I.A. Khan, S. Koul, P.L. Sangwan, D.M. Mondhe, U. Nandi, G. Singh, M.K. Tikoo, S. Sharma, A. Wani, S. Rath, S. Singh, M.J. Mintoo, R.A. Vishwakarma Methods of enhancing bioavailability/ bioefficacy of drugs and pharmaceutical compositions thereof Filed (IN 201911047260) 2019
R.K. Johri, S.T. Abdullah, K. Singh, D.K. Gupta, B.K. Kapahi, D.M. Mondhe, S.M. Jain, O.P. Suri, K.L. Bedi, G.N. Qazi Herbal hapatocurative agent against CYP450 and free radical mediated drugs toxicity (including-tubercular drugs). NF53 2002
S. Koul, M.V. Reddy, T. Niranjan, J.L. Koul, P.L. Sangwan, S.C. Taneja, I.A. Khan, A. Kumar, N.P. Kalia, S.T. Abdullah, R.K. Johri, S.S. Pagoach, A.K. Tikoo, M.K. Tikoo, A.K. Saxena, S.K. Agrawal, D.M. Mondhe, S.K. Agrawal, B. Purnima, S. Sharma, S. Singh, G.D. Singh, S. Bhusari, G.N. Qazi

 

  Novel aromatic amides as potentiators of the bioefficacy of drugs NF0113 2008
S.B. Bharate, A. Kumar, J. Bharate, P. Joshi, A. Wani, R. Mudududdla, R. Sharma, R.A.  Vishwakarma Polyprenylated phloroglucinol compounds as potent P- glycoprotein inducers US Patent Number: US 10,202,326 B2 2019
S.B. Bharate, A. Kumar, S. Manda, P. Joshi, S.S. Bharate, A. Wani, S. Sharma, R.A. Vishwakarma Alkylidene Phosphonate esters as P-glycoprotein inducers  US Patent number: US 10 377, 781 B2

 

 

 2019