1. Biopharmaceutics & Pharmacokinetics-4

2. Journey of Oral Drugs through GIT
Large Intestine
Small Intestine
Stomach
Mouth
Drug travels through different region in GI tract
Tract is almost 4.5 m long
Each region is different in anatomy, pH, function
All these factors affect the drug absorption
DCT: only 10 % reabsorbed, impermeable to water, leads to further dilution of filtrate

3. Mouth Small surface area for drug absorption Typical pH = 6.8
Directly absorbed in to blood circulation
Drugs absorbed:
Neutral
Slightly basic
lipophilic
DCT: only 10 % reabsorbed, impermeable to water, leads to further dilution of filtrate

4. Stomach Bag like structure, smooth surface
Typical pH = (HCL secretion)
Acidic drugs:
Un-ionized so can be absorbed if it dissolves
Basic drugs:
Acidic environment helps in dissolution as the drugs are ionized
Ionised drug however limits absorption
DCT: only 10 % reabsorbed, impermeable to water, leads to further dilution of filtrate

5. Why is Stomach NOT a major site for absorption ??
Area: Total surface area for absorption is small
Nature of Epithelium: Most of the cells are secretion cells (mucus secreting) & not absorption
Gastric Residence Time: Drug stays in stomach for limited time affecting absorption
DCT: only 10 % reabsorbed, impermeable to water, leads to further dilution of filtrate

6. Small Intestine Major site of absorption for most of drugs
Very large surface area
Folds – Villi – Micro-villi lead to almost 600 times increase in surface area
DCT: only 10 % reabsorbed, impermeable to water, leads to further dilution of filtrate

7. Why is Small Intestine a major site for drug absorption
Large Surface area: Structural arrangement of folds, villi & microvilli increase the surface area X 600 times
Long Length: long length results in increased total area compared to stomach
Greater Blood flow: almost 6 – 10 times greater than stomach
Favorable pH: Range is 5 – 7.5, most drugs Un-ionized in this range, increased absorption
Slow peristaltic movement & high permeability

8. Large Intestine
Length, surface area (No Villi) very small compared to small intestine
pH : neutral or slightly alkaline
Long residence time (6-12 hr) might help in absorption of poorly soluble drugs/sustained release
Major role in absorption of water/electrolytes
DCT: only 10 % reabsorbed, impermeable to water, leads to further dilution of filtrate

9. Physiological Factors affecting Drug Absorption
Gastric Emptying:
Passage of drugs from Stomach to Small Intestine
This movement can be rate limiting as major absorption of drugs in small intestine
Different parameters to measure gastric emptying:
Gastric empting rate
Gastric emptying time
Gastric emptying half life
Typical gastric time: 1-2 hours
Pyrolic sphincter, opens up, only allows well emulsified food (<2 mm), intestine food control, contracts to have food pushed inside
Dissolution/absorption, gastric emptying promoted on empty stomach, so lots of oral studies require empty stomach

10. Factors affecting “Gastric Emptying”
Volume of Meal
Larger meal , longer emptying time
Composition of Meal
Carbohydrates > Proteins > Fats
Physical state/Viscosity of Meal
Liquids > Solids
Temperature of Meal
High or low temp of food slows gastric emptying
Gastrointestinal pH
Slow at low pH, higher at alkaline

11. Factor affecting “Gastric Emptying”
Electrolytes & Osmotic pressure
Isotonic, water show rapid while high electrolyte conc slows gastric emptying
Body posture
Standing, lying on right side promotes
Emotional state
Stress/anxiety promotes gastric motility while depression slows movement
DCT: only 10 % reabsorbed, impermeable to water, leads to further dilution of filtrate

12. Factor affecting “Gastric Emptying”
Exercise
Vigorous training slows gastric emptying
Disease state
Gasteroenteritis, gastric ulcer, pyloric stenosis, diabetes - slows gastric emptying
Partial/total gastrectomy, duodenal ulcer, hyperthyroidism - promotes gastric emptying
DCT: only 10 % reabsorbed, impermeable to water, leads to further dilution of filtrate

13. Factors affecting “Gastric Emptying”
Drugs
That promote gastric movement: Metoclopramide, domperidone, cisapride
That inhibit gastric movement: Antacids, anti-cholinergics, narcotic analgesics, tricyclic antidepressants
DCT: only 10 % reabsorbed, impermeable to water, leads to further dilution of filtrate

14. Gastric emptying Rapid emptying advised where Rapid onset desired
Dissolution in intestine (enteric)
Drugs unstable in stomach
Drugs best absorbed from distal small intestine
Delay in gastric emptying advised where
Food promotes dissolution/absorption
Disintegration/dissolution promoted by gastric fluids
Drugs that dissolve slowly
DCT: only 10 % reabsorbed, impermeable to water, leads to further dilution of filtrate

15. Time in Intestine (Intestinal Transit)
Since most absorption in small intestine, longer stay promotes absorption of drugs
Peristaltic movement promotes absorption by better membrane contact, agitation (promotes dissolution)
Longer stay is preferred for drugs
Dissolve slowly, release slowly
Dissolve only in intestine
Absorbed from specific sites
Absorption through mucosa is slow
Absorption from colon is minimal
Intestinal Region
Typical transit time
Duodenum
5 min
Jejunum
2 hrs
Ileum
3 – 6 hrs
Caecum
0.5 – 1 hrs
Colon
6 – 12 hrs
Peristaltic movement promotes solbilization in intestine

16. Gastrointestinal pH
Wide range on pH, affect absorption through various effects
Disintegration
Enteric coated formulations
Dissolution
pH affects dissolution of drugs
pH affects solubility of weak base/acids
DCT: only 10 % reabsorbed, impermeable to water, leads to further dilution of filtrate

17. Gastrointestinal pH
Wide range on pH, affect absorption through various effects
Absorption
Drug pka, surrounding pH determine ionic state of drug
Non-ionized drug primarily absorbed
Stability
Acidic environment can affect stability of drugs
Ex penicillin, Erythromycin are enteric coated formulations
DCT: only 10 % reabsorbed, impermeable to water, leads to further dilution of filtrate

18. Disease state affecting drug absorption
GI diseases & infections
Celiac disease leads to malabsorption due to
Increased gastric emptying rate
Altered intestinal metabolism, permeability
Impaired secretion of bile
Crohns disease leads to malabsorption due to
Altered intestinal metabolism
Decreased gut surface area
Decreased intestinal transit time
Gastric surgeries
Celiac disease is a condition that damages the lining of the small intestine and prevents it from absorbing parts of food that are important for staying healthy
Crohn's disease is a form of inflammatory bowel disease (IBD). It usually affects the intestines, but may occur anywhere from the mouth to the end of the rectum (anus)

19. Disease state affecting drug absorption
Cardiovascular diseases
Cardiac failure affects bioavailability by
Oedema of intestine
Altering pH
Affecting peristaltic movement
Gastric emptying
Altering blood flow
Hepatic diseases
Conditions of hepatic failure (cirrhosis) affects drug bioavailability
Reduces overall first-pass effect
Propranolol undergoes high first pass effect
Shariq AIKC/FinalYB/2014

20. Blood flow to GIT
GIT track extensively perfused by blood/lymphatic system
Almost 28 % of cardiac output to GIT (Splanchnic circulation)
High perfusion rate ensures “sink conditions’
External conditions affect blood flow (drugs, food)
DCT: only 10 % reabsorbed, impermeable to water, leads to further dilution of filtrate

21. Gastrointestinal Contents
Food-drug interactions:
Food can affect absorption
Can increase OR decrease absorption
In general drugs absorbed better under fasting conditions
Delay/Decrease in absorption
Delay in gastric emptying
Formation of poorly soluble complex
Increased viscosity
Increase in absorption
Increased time for dissolution
Enhanced solubility (bile secretion)
Prolonged residence time
DCT: only 10 % reabsorbed, impermeable to water, leads to further dilution of filtrate

22. Gastrointestinal Contents
Fluid Volume:
Large volume facilitates dissolution, absorption
Drug-Drug interactions:
Can be either physico-chemical or physiological
Physico-chemical:
Adsorption
Complexation
pH change
DCT: only 10 % reabsorbed, impermeable to water, leads to further dilution of filtrate

23. Gastrointestinal Contents
Drug-Drug interactions:
Physiological:
Decreased GI transit : Drugs slow GI movement & promote absorption
Increased gastric emptying: prokinetic drugs promote emptying improving absorption
Altered GI metabolism: Antibiotics affect GI microbial flora affecting overall bioavailability of drugs
DCT: only 10 % reabsorbed, impermeable to water, leads to further dilution of filtrate

24. THANK YOU -PHARMA STREET