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Modern Insights into Pharmacokinetics and Drug Discovery

Explore the latest advancements in pharmacokinetics, drug interactions, and holistic drug discovery strategies presented by Professor Bhushan Patwardhan from Savitribai Phule Pune University. Gain valuable insights into the evolving landscape of evidence-based Ayurveda and pharmaceutical sciences.

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Modern Insights into Pharmacokinetics and Drug Discovery

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  1. Evidence-based Ayurveda Pharmacodynamics and Pharmacokinetics Professor Bhushan Patwardhan, PhD, FAMS Interdisciplinary School of Health Sciences Savitribai Phule Pune University bpatwardhan@gmail.com Standing on the Shoulders of Giants, CCRAS Orientation Training on Management and Personality Development, March 15, 2017 Patwardhan - CCRAS-15/03/2017

  2. Pharmacokinetics (PK) and Pharmacodynamics (PD) • Pharmacokinetics and Pharmacodynamics broadly covers Absorption, Distribution, Metabolism, Elimination and Toxicity - ADMET • It is about mechanism of actions and herb-drug or drug-drug interactions. • This is the way for FDA approved prescription drugs for global use Patwardhan - CCRAS-15/03/2017

  3. Pharmacokinetics, Herb-drug Interactions and Phytochemical Standardization Present Situation Patwardhan - CCRAS-15/03/2017

  4. Choi et al, JACM, 2015 Patwardhan - CCRAS-15/03/2017

  5. Patwardhan - CCRAS-15/03/2017

  6. Patwardhan - CCRAS-15/03/2017

  7. Patwardhan - CCRAS-15/03/2017 Choi et al, JACM, 2015

  8. Drug Discovery Present situation • Drugs are failing for several reasons making any Pharmacopeia as an extremely dynamic document. •  Drugs fail due to toxicity, untoward events and other serious safety related issues, microbes or systems resistance or because the target gets modulated. • Starting with Thalidomide in the 1950 till today, hundreds of drugs have been banned by the regulators and were withdrawn from markets. • Drug acting on specific target can actually trigger a butterfly effect. Patwardhan - CCRAS-15/03/2017

  9. Decade of Drug Recalls Patwardhan - CCRAS-15/03/2017

  10. 1984 Statin Story 2014 Patwardhan - CCRAS-15/03/2017

  11. What is happening??? Are the days of NCE numbered??? Do we need a fresh approach??? Patwardhan - CCRAS-15/03/2017

  12. Web of causation Patwardhan - CCRAS-15/03/2017 Patwardhan, Mutalik, Tillu, Integrative approaches for health: Biomedical research, Ayurveda and Yooga, Elseverr 2015

  13. Magic Bullets?? Expecting too much Symptoms Patwardhan - CCRAS-15/03/2017

  14. Combinatorial and Holistic Approach:The Most Modern View Multitargeted drugs: The end of the ‘one-target-one disease philosophy? • The preparation of dual- or multiple-ligands on an almost rational basis is now conceivable and it can be expected that many of these molecules will yield drugs of superior clinical value compared with mono-target formulations. Camille Wermuth, Drug Discovery Today 19, October 2004 5-Jan-20 Patwardhan - CCRAS-15/03/2017

  15. Shifting the Focus Patwardhan - CCRAS-15/03/2017

  16. Systems Biology Approach • Drug Discovery NOT in Isolation • Syndromes and not just Diseases • Intentional therapy and not coincidental • Metabolomics and Pharmacogenomics • Holistic: Prakriti-Disease-Drug 5-Jan-20 Patwardhan - CCRAS-15/03/2017

  17. Metabolism Knowledge Yesterday Patwardhan - CCRAS-15/03/2017

  18. Google Map of Human Metabolic Networks Patwardhan - CCRAS-15/03/2017

  19. Metabolism Knowledge Today • UC San Diego built the first virtual reconstruction of the human metabolism network in 2007 • Recon 1, featured more than 3,300 known biochemical reactions documented in over 50 years of metabolic research. • Recon 2, contains more than 7,400 reactions, almost 1,800 genes of an estimated 20,000 protein-coding genes in the human genome.  Patwardhan - CCRAS-15/03/2017

  20. Pharmacology Receptors & Drugs Agonists & Antagonists Stimulants & Suppressants Dose - Response Relationships Patwardhan - CCRAS-15/03/2017

  21. Network Pharmacology • Genes-Targets-Drugs • Molecular Mechanisms • Systems Biology • Synergism • Formulations Patwardhan - CCRAS-15/03/2017

  22. Advantage Ayurveda Patwardhan - CCRAS-15/03/2017

  23. Pharmacokinetics and PharmacodynamicsNetwork Pharmacology, Multi Targeting Case studies from Ayurvedic medicine Patwardhan - CCRAS-15/03/2017

  24. : Examples of Opportunity Phyllanthus & Hepatitis Potential candidates Ashwagandha Guduchi Shatavari Nisha Amalaki Brahmi Patwardhan - CCRAS-15/03/2017

  25. Curcuma longa Ayurvedic description Biological targets: Aryl hydrocarbon receptor, Cytochrome P450 enzymes, Glutathione S-transferase, kinases, COX, iNOS, MMP Therapeutic class: Cancer, Inflammation, DiabetesandChemo prevention Aggarwal B, Healing Spices, 2114. Curcumin Patwardhan - CCRAS-15/03/2017

  26. Ashwagandha – Rising Star? A comparative pharmacological investigation of Ashwagandha and Ginseng Anuradha Grandhi,  A.M. Mujumdar, Bhushan Patwardhan, Journal of Ethnopharmacology, 1994, 44, 3, 131-135. Patwardhan - CCRAS-15/03/2017

  27. Triphala: An Intelligent Formulation Patwardhan - CCRAS-15/03/2017

  28. Pharmacology Network Triphala, Ashwagandha Patwardhan - CCRAS-15/03/2017

  29. Effect and Molecular Mechanism of Arjuna and its Formulation in T2DM and F1 generation from Gestational Diabetic mothers Patwardhan - CCRAS-15/03/2017

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  31. Molecular Mechanism of Arjuna Rasayana and its formulation MWR + HFD Terminalia arjuna Rasayana TA ↑↑Adiposity Pre-A MA TA Arjunarisht A TA TA A TLR-4 IL-6 TNF-α TA Insulin Glucose IR Iκ-κB IRS-1 Glut-4 Glucose A NF-κB AMPK Sirt-1 PPAR-γ SOCS-3 PGC-1α TA A JAK-STAT-3 TA A TA A Lep-R Adipoq--R GLB Glibenclamide MET Metformin TZD Thiazolidinediones GLB MET TZD Patwardhan - CCRAS-15/03/2017

  32. Chemoprofiling & Batch Reproducibility: Tinospora cordifolia case example HPLC chromatogram HPLC-ESI-MS chromatogram Protoberberine alkaloids jatrorrhizine, palmatine and berberine identified using HPLC-DAD and HPLC-ESI-MS method Patwardhan - CCRAS-15/03/2017

  33. Chemoprofiling & Batch Reproducibility: 1. Tinospora cordifolia case example TCE batch II TCE batch I Patwardhan - CCRAS-15/03/2017

  34. Chemoprofiling & Batch Reproducibility: Asparagus racemosus case example Selection of precursor and daughter ion for MRM MS/MS of Shatavarin IV MS/MS of Withaferin A (internal std) Shatavarin IV identified using HPLC-ESI-MS/MS with MRM Patwardhan - CCRAS-15/03/2017

  35. Storage condition Real time: 30 ± 20C/65 ± 5% RH Accelerated: 40 ± 20C/75 ± 5% RH Evaluation: 1. Physical Properties: Physical form Moisture content Particle size 2. Chemical properties: Change in total fingerprint (Pearson correlation coefficient) Change Marker content analysis 3. Biological properties: Change in % immuno-modulatory activity Stability testing: Withania case example Free flowing powder at zero month Patwardhan - CCRAS-15/03/2017

  36. Stability testing: Withania case example HPLC-DAD fingerprint HPLC-ESI-MS fingerprint MS of Withaferin A MS of Withanolide A LC-ESI-MS of WSE Withanolide A Withaferin A WSE chromatogram LC-ESI-MS of Reference Patwardhan - CCRAS-15/03/2017

  37. Effect of Metformin (MET) alone and co-administered with Nisha Amalaki (NA) and Curcuminoids (CE) on Mean plasma MET concentration-time profile normal and diabetic animals (N=4). Results are expressed as mean ± SEM Patwardhan - CCRAS-15/03/2017

  38. Effect of Metformin (MET) alone and co-administered with Nisha Amalaki (NA) and Curcuminoids (CE) on OGTT in diabetic animals (A) blood glucose levels and (B) AUC0-180 min. Results were expressed as mean ± SEM. *p<0.05 and ***p<0.001 as compared to diabetic control Co-administration of NA+MET and CE+MET resulted in beneficial PK and PD interactions leading to antihyperglycemic and antihyperlipidemic effects. PK interaction of NA+MET and CE+MET are drastically different in diabetes and normal conditions suggesting the importance of disease system approach. Patwardhan - CCRAS-15/03/2017

  39. Botanical-Drug Interactions Pharmacodynamic interactions • Con-current use of botanicals with prescription is increased • Rises the incidences for botanical-drug interactions • Pharmacokinetic or pharmacodynamic types • May be beneficial or has risk • Evidence based research for evaluation of medicinal plants for such interactions is urgently needed Pharmacokinetic interactions Patwardhan - CCRAS-15/03/2017

  40. Evaluation of pharmacokinetic botanical-drug interactions • Traditional hydro-alcoholic extract did not show any significant effect on MET PK; however, the SFCE caused a significant reduction in absorption of MET. • Combined use of MET with SFCE should be avoided Patwardhan - CCRAS-15/03/2017

  41. Impact on CYP 3A4 inhibition • ARE, WSE showed no inhibition while TCE shows mild inhibition • Pure compounds such as berberine, palmatine and jatrorrhizine showed strong inhibition • The order of CYP3A4 inhibitory potential: Ketoconazole > berberine > jatrorrhizine > palmatine > TCE > ARE > WSE ARE, WSE and TCE preparedas per traditional method did not show significant CYP3A4 inhibition suggesting safe use as dietary supplements or adjuvant during cancer chemotherapeutics Patwardhan - CCRAS-15/03/2017

  42. Pharmacokinetic evaluation of withanolides • The validated method was successfully applied to a PK estimation of WA and WLD in mice plasma following oral administration of W. somnifera root aqueous extract. • Withanolides have rapid oral absorption started within 10 mins after administration. The PK study has revealed that WA has one and half times more relative bioavailability as compared to WLD Patwardhan - CCRAS-15/03/2017

  43. Key Factors for Evidence-Based Ayurveda Pharmacopoeia Monographs for Drugs and Formulations Standardization and Quality Control Safety, Toxicity, Pharmacodynamic, Non Clinical Documentation of Clinical Practice Patwardhan B, EPMA Journal 2015 Patwardhan - CCRAS-15/03/2017

  44. Thank you CCRAS “Ayurveda owes its call not to selfish goals or worldly pleasure, but to compassion for fellow beings. In seeking to know my legacy, you have but seen the leaves of a universal tree, too vast for your eyes. May your sight grow and your quest never end”… The Legacy of Caraka, M.S. Valiathan Patwardhan - CCRAS-15/03/2017

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  47. Global Recognition of Traditional Medicine and Natural Products Youyou Tu, Noble Laureate, Chinese Academy of Traditional Medicine Patwardhan - CCRAS-15/03/2017

  48. Ayurveda: The Discovery Engine • 4000 years of living tradition • Over 300 well documented and in-use medicinal plants, sound philosophical and rational base • Over 5000 traditional formulations in practice • A large experimental database available based on earlier CDRS of ICMR, CSIR and other laboratories • Food, Diet, Drugs, Lifestyle Three Clear Paths: • Botanical drugs &b Phytopharmaceuticals- FDA • Ayurvedic & Herbal medicines -AYUSH • Ayurceuticals and Health supplements - FSSAI Are we globally competent? Patwardhan - CCRAS-15/03/2017

  49. Indian traditional health Knowledge:Needs strategic vision, scientific research and systematic efforts Patwardhan - CCRAS-15/03/2017

  50. Phyllanthus & Hepatitis: Delayed opportunity Patwardhan - CCRAS-15/03/2017

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