GI Tract - STOMACH
• Gastric emptying and acid secretion controlled by vagus nerve, local nerve plexus, hormones, chemo-receptors and stretch receptors
• Fasting pH = 2-6.
• In presence of food: Gastric distension and peptides stimulate gastrin and histamine release. These cause parietal cells to release H+ / pH lowers to 1-2
-Emptying is influenced by nature of food content and osmolarity
Small Intestine
-Duodenum: Common bile duct from pancreas and gallbladder empties into intestines here, pH is 6-7, contains pancreatic enzymes for digestion of proteins, carbs, fats, esters
-Jejunum: Common site of drug absorption
-Ileum: Together with jejunum is a common site for absorption of amino acids, water soluble vitamins, specific sugars by facilitated transport processes
• Terminal part contains bacteria at a concentration much less than that in the large intestine
Large Intestine
-Bacteria abundant, up to 1012 bacteria per mL
• Some drugs decomposed here
• Colon: Lacks villi and has limited drug absorption, Lined with mucin, pH of 5.5-7.0, Only drugs that are well absorbed in this region are candidates for modified (extended)-release dosage forms
Release Characteristics of Dosage Form (rate of abs. in GI tract)
-Disintegration / deaggregation
-Dissolution of drug from granules
• Also dependent on inactive ingredients and formulation variables
Physicochemical Properties of Drug (rate of abs. in GI tract)
- Complexation
- Ionization (acid/base)
- Partition coefficient (octanol/water)
- Solubility in water
Physiology of Gastrointestinal Tract (rate of abs. in GI tract)
- Colonic retention
- Gastric emptying
- Intestinal motility
- Perfusion of the gastrointestinal tract • Permeability of gut wall
Gastrointestinal Tract Abnormalities and Diseases (rate of abs. in GI tract)
- Crohn’s disease
- Diarrhea
- Gastric resection or modification -bypass- (e.g., in obesity)
- Ulcerative colitis
Transit Time of Nondisintegrating Pellets in Stomach, Small Intestine, and Colon.
- Intersubject Variability
• The transit time of small and large nondisintegrating pellets are shown in the following figure - Intrasubject Variability
• The gastric emptying and colonic filling of small pellets, see next Figure, demonstrates the variability in the transit through the stomach and small intestine within the same subject under fed (light breakfast) conditions
Transit Time: Colon
- varies from 6 hours to several days with an average of about 12-30 hours
- with diarrhea the transit can be just a few hours, while in severe constipation it can be 5 or more days
- overall time in the colon is much greater than in the stomach and small intestine combined and can be highly variable
- a nondisintegrating pellet spends about 80% of its total time in the gastrointestinal tract within the colon
Transit Time (colon): Has Major Implications for…
• enterically-coated tablets (do not erode at low pH of stomach)
• modified-release (sustained-release dosage forms which stay pretty much intact down the GI tract)
-For drug released after 4-5 hours:
• If fasting, will likely be absorbed in colon
• With food, time to reach colon is longer
Gastric Emptying (rate of drug abs.)
-All drugs (acids, bases, neutrals) in solution are absorbed faster from intestine than stomach, irrespective of pH
-Hence, any factor affecting the rate of gastric emptying will influence the absorption kinetics of a drug given orally in solution
• Drugs: some slow gastric emptying and some hasten it with corresponding changes in absorption kinetics of drugs
Gastric Emptying: Fasted vs. Meals
- Fasted Stomach: Small (< 5mm) and large (> 5mm) nondisintegrating pellets = relatively rapid. Large nondisintegrating solids = more erratic and variable
- Meals: Meals, and fats in particular, markedly delay gastric emptying of large nondisintegrating pellets (> 5mm); meals also delay emptying of liquid and small solids. Little effect of meals on small intestine transit time, 2.5 to 4 hours
Impact of Gastric Emptying
- Depends on drug and pharmaceutical system
- Proton pump inhibitors, azithromycin, and didanosine are rapidly hydrolyzed to inactive products in the acidic environment of the stomach
- Aspirin, sulfasalazine, and bisacodyl are gastric irritants = Solution? Enteric Coating: coat with material resistant to acidic environment of stomach but which breaks down in the intestinal fluids
- For large coated tablet: Fasted -Intact tablet passes from the stomach into intestine in 20 min to several hours. Fed - Up to 12hr or more
Enteric Coating
- Enteric-coated products cannot be used when rapid and reliable absorption is required
- Enteric-coated small granules is an improvement because the rate of delivery of the granules to the intestine is more reliable, being less dependent on a single event, a “house- keeping wave”, and on food intake
Lipophilic Drug (sparingly soluble)
• By retaining in stomach, increasing bile excretion and by prolonging dissolution in the upper gastrointestinal tract, may increase overall oral absorption
Drugs that are unstable in the gastric milieu
- May undergo much greater decomposition when coadministered with food, especially fats
- Due to being exposed to low pH for longer periods of time
Water & Fasting
• Generally the rate of absorption in the fasted state is faster and the bioavailability sometimes more complete when the drug is taken with large, rather than small, volumes of water
PERMEABILITY OF GASTRO-INTESTINAL MEMBRANES
- Drug Transport: Absorption into the systemic circulation from the gastrointestinal tract requires movement through membranes.
- Transcellular absorption = when the drug moves through cells
- Paracellular absorption = go through gaps between cells (Some small polar molecules are not able to traverse the cell membranes)
- Some drugs, of course, may undergo both processes.
The overall movement across the functional membrane depends on:
- Diffusion and Convection - surface area, permeability, lipophilicity, charge, perfusion
- Carrier Mediated Transport: membranes maintain the internal cellular environment by excluding or removing some materials and sequestering or selectively retaining vital substances (many polar compounds with low lipid solubility penetrate membranes much faster than anticipated for passive diffusion through an inert lipoidal barrier)
Passive facilitated diffusion
Examples: movement of glucose into erythrocytes, intestinal absorption of nucleosides and nucleobases
-Passive process
• substance moves down a concentration gradient without net expenditure of energy
• At equilibrium, concentrations in and surrounding the cells remain constant over time
• At high plasma glucose concentration, for example, the rate of its transport into the erythrocyte reaches a limiting
value or transport maximum
Equilibrating Transporters
Furthermore, in common with other carrier-mediated systems, glucose transport is reasonably specific and is inhibited by other substrates
• Relatively few drugs undergo passive facilitated diffusion.
• These transport systems are called “Equilibrating Transporters.”
Active transport
-Characteristics in common with passive facilitated diffusion are saturability, specificity, and competitive inhibition
- Active transport is distinguished from passive facilitated diffusion by the net movement of a substance against a concentration gradient, which can be large
• Maintenance of this gradient requires metabolic energy
• Active transport can therefore be impeded by metabolic inhibitors
Concentrating Transporters
(active transport cont.)
These transport systems are called “Concentrating Transporters”
• Influx transporters = those that facilitate transport into cells
• Efflux transporters = those that facilitate movement out of cells
