Enhancing Drug Bioavailability by Overcoming Intestinal Metabolism

1. Enhancing Drug Bioavailability by Overcoming Intestinal Metabolism Dr. Basavaraj K. Nanjwade M.Pharm., Ph.D Professor of Pharmaceutics Department of Pharmaceutics KLE University, Belgaum, India E-mail: bknanjwade@yahoo.co.in Cell No: 00919742431000

2. INTRODUCTION • Drugs may be given in a number of ways • Oral administration is the most common and the easiest way to give a drug • The amount of drug reaching the general circulation will depend on a number of factors • The proportion of drug that reaches the target organs and tissues, which is expressed as a % of the dose administered. BIOBIO-2010, Hyderabad

3. Intestinal Absorption of Oral Drugs Active Transport Passive Diffusion • Nutrients (small peptides, amino acids, vitamins, fatty acids, etc.) • Selected drugs: valacyclovir, ACE inhibitors cephalosporins, pravastatin, etc. • Most approved oral drugs BIOBIO-2010, Hyderabad

4. Drug Absorption • The drug is absorbed from the GI tract and passes via the portal vein into the liver where some drugs are metabolized • Sometimes the result of first pass metabolism means that only a proportion of the drug reaches the circulation • First pass metabolism can occur in the gut and liver BIOBIO-2010, Hyderabad

5. Drug Absorption • Absorption is the process by which a drug enters the bloodstream without being chemically altered or The movement of a drug from its site of application into the blood or lymphatic system BIOBIO-2010, Hyderabad

6. Drug Absorption • Factors which influence the rate of absorption • types of transport • the physicochemical properties of the drug • protein binding • routes of administration • dosage forms • circulation at the site of absorption • concentration of the drug BIOBIO-2010, Hyderabad

7. Drug Absorption • The rate at which a drug reaches it site of action depends on: • Absorption- involves the passage of the drug from its site of administration into the blood • Distribution - involves the delivery of the drug to the tissues BIOBIO-2010, Hyderabad

8. Drug Absorption • Mechanisms of solute transport across membranes • passive diffusion • filtration and bulk flow • endocytosis • ion-pairing • active transport • Drug Absorption animaton BIOBIO-2010, Hyderabad

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10. Bioavailability Definition: the fraction of the administered dose reaching the systemic circulation for i.v.: 100% for non i.v.: ranges from 0 to 100% e.g. lidocaine bioavailability 35% due to destruction in gastric acid and liver metabolism First Pass Effect BIOBIO-2010, Hyderabad

11. Bioavailability Destroyed by gut wall Destroyed in gut Not absorbed Destroyed by liver to systemic circulation Dose BIOBIO-2010, Hyderabad

12. The enterohepatic shunt Drug Liver Bile formation Bile duct Biotransformation; glucuronide produced Hydrolysis by beta glucuronidase gall bladder Portal circulation Gut BIOBIO-2010, Hyderabad

13. First-pass Effect BIOBIO-2010, Hyderabad

14. (AUC)o (AUC)iv Bioavailability = i.v. route Plasma concentration oral route Time (hours) BIOBIO-2010, Hyderabad

15. Enzymatic status • Luminal enzymes of the small intestine - Pepsin is the primary enzyme found in gastric fluid. - Other enzymes such as lipases, amylases and peptides are secreted into the small intestine via the pancreas in response to ingestion of food. - Pepsins and proteases are responsible for the breakdown of protein and peptide drugs in the lumen. - Drugs which resemble nutrients such as fatty acids and nucleotides are susceptible to enzymatic attack. BIOBIO-2010, Hyderabad

16. Enzymatic status • Colon - Presence of bacterial enzymes in the colonic region of the gastrointestinal tract, which digest material not yet digested in the small intestine. BIOBIO-2010, Hyderabad

17. First-pass Effect • The first-pass effect is the term used for the hepatic metabolism of a pharmacological agent when it is absorbed from the gut and delivered to the liver via the portal circulation. • The greater the first-pass effect, the less the agent will reach the systemic circulation when the agent is administered orally BIOBIO-2010, Hyderabad

18. First-pass Effect cont. Magnitude of first pass hepatic effect:Extraction ratio (ER) ER = CL liver / Q ; where Q is hepatic blood flow (usually about 90 L per hour). Systemic drug bioavailability (F) may be determined from the extent of absorption (f) and the extraction ratio (ER): F = f x (1 -ER) BIOBIO-2010, Hyderabad

19. Bypassing First Pass Metabolism • Two ways to bypass first pass metabolism involve giving the drug by sublingual and buccal routes • The drugs are absorbed by the oral mucosa in both methods • In sublingual administration the drug is put under the tongue where it dissolves in salivary secretions BIOBIO-2010, Hyderabad

20. Bypassing First Pass Metabolism • Nitroglycerine is administered in this way • In buccal administration the drug is placed between the teeth and the mucous membrane of the cheek • Sublingual and buccal methods both avoid destruction by the GI fluids and first pass effect of the liver BIOBIO-2010, Hyderabad

21. Improving oral Bioavailability • Particle Size Reduction - Jet-milling, high energy ball milling - Spray drying - Super critical fluid extraction - High supersaturation crystallization • Solid Form Thermodynamics - Amorphous - Salts - High Free Energy Polymorphs • Improve Solubility BIOBIO-2010, Hyderabad

22. Attempted oral delivery systems • Enzyme inhibition - Difficult to target large variety of enzymes - Interferes with natural metabolism • Permeation enhancement - Leads with non-specific paracellular transport • Enteric coatings - pH dependent solubility - Maintain integrity through stomach, degrade in intestine - Modest success, but still very low transport BIOBIO-2010, Hyderabad

23. High pH pKa ~ 4.8 Low pH Insulin Complexation hydrogels • Poly(methacrylic acid-g-ethylene glycol), P(MAA-g-EG) • MAA backbone grafted with terminally functional PEG chains • Forms a water swollen, cross-linked polymer network • Exhibits environmentally responsive pH dependent swelling PMAA PEG BIOBIO-2010, Hyderabad

24. Approach • Improve bioavailability of the oral delivery system by modifying the network of the P(MAA-g-EG) hydrogel and combining it with chemically modified insulin species • Insulin modification: - PEGylated insulin can resist enzymatic attack - Use Vitamin B12 to enhance transport across intestinal wall BIOBIO-2010, Hyderabad

25. Insulin conjugation • PEGylation: Covalent attachment of PEG to a protein • Reduces enzymatic degradation of protein • Increases circulation time • Increases solubility of protein • Would help overcome enzymatic barrier in intestine • May enhance interaction between hydrogel and insulin • PEG could be used as a linking agent for Vitamin B12 • Vitamin B12 is actively transported across epithelial cells • May provide pathway to overcome physical barrier in the intestines BIOBIO-2010, Hyderabad

26. Summary of Polymers used in pharmaceutical formulations as coating materials. BIOBIO-2010, Hyderabad

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28. Anatomical Considerations Gut Lumen Portal Vein Liver Gut Wall Systemic Circulation Metabolism Metabolism Release + Dissolution Permeation Elimination Absorption Bioavailability BIOBIO-2010, Hyderabad

29. Limited Capacity Absorption Window Small Intestine Colon Stomach 1 to 6 hours 2 to 4 hours 8 to 18 hours Gabapentin Has a Limited GI Absorption Window Transit Time in Humans • Saturable uptake – exposure not proportional to dose • Variable capacity/transit times - inter-subject variability in PK • No colonic absorption - SR formulation not possible BIOBIO-2010, Hyderabad

30. High Capacity Transporter Small Intestine Colon Stomach 1 to 6 hours 2 to 4 hours 8 to 18 hours Overcoming a Limited Absorption Window Modify the drug for recognition by high capacity transporters located throughout the intestine: Increased bioavailability Greater dose proportionality Lower inter-patient variability Reduced dosing frequency (sustained release) BIOBIO-2010, Hyderabad

31. THANK YOU BIOBIO-2010, Hyderabad