Drug Absorption Continued Part 2 Flashcards
What are enterocytes?
are Simple columnar epithelial cells that Lines intestinal walls
they contain Drug transporters
Tight junctions between enterocytes limit the passage of drugs through the paracellular route (between cells).
contain drug-metabolizing enzymes (like CYP3A4) that metabolize drugs before they enter circulation, reducing their bioavailability
What are the types of drug transport?
Passive Diffusion
Carrier-mediated transport
Vesicular transport
Pore (Convective) transport
Ion-pair formation
Paracellular drug absorption (500MW)
What are the types of Carrier-mediated transport
Explain Carrier-mediated transport
Active transport
Facilitated Diffusion
Energy Dependent: Uses ATP to actively pump substances across membranes.
Membrane Bound: Located in the plasma membrane of various cells
Efflux Transporter: works to expel drugs
Defense Mechanism: Protects tissues by limiting drug absorption (accumulation) and facilitating drug excretion.
Explain active transport
Carrier-mediated trans-membrane process
Against concentration gradient
Requires a carrier molecule
Similar structure drugs – compete
Saturation ( can become saturated with high concentration)
Explain facilitated diffusion
Carrier-Mediated Transport: Requires a specific transporter protein embedded in the membrane.
Substances move from high to low concentration.
No Energy Required.
Structurally Selective: The transporter recognizes specific molecules based on their structure.
Saturable: Transport rate is limited by the number of available carrier proteins.
Competitive Inhibition: Similar drugs or molecules compete for the same transporter, affecting absorption.
Minimal Role in Drug Absorption: Since it relies on a gradient and does not actively concentrate drugs, its impact on overall drug absorption is limited compared to active transport mechanisms.
What are the the two types of intestinal transporters?
Uptake/Influx transporters - promotes absorption
Efflux transporters - hinders absorption
(defense mechanism for cell)
What are the main genetic superfamilies of drug transporters?
Are they influx or efflux?
Give examples
- ATP-binding cassettes (ABC)
are efflux transporters - Solute carrier (SLC)
are both influx and efflux
Efflux :
1. MDR1 (P-gp) – ABCB1
2. BCRP – ABCG2
Influx :
PEPT1
What is Vesicular Transport?
Give Examples
Process of engulfing particles or dissolved materials by the cell
Pinocytosis – engulfment of small solutes or fluids
Phagocytosis – engulfment of larger particles or macromolecules
Endocytosis/exocytosis are the processes of moving specific macromolecules
Explain Pore (Convective) Transport
Crossing of very small molecules (urea, water) of cell membranes
Unlike carrier-mediated transporters, pore-forming proteins create aqueous open channels that permit small molecules to pass freely by diffusion
e.g aquaporins, ion channels
Explain Ion-Pair Formation
Highly ionized molecules have Poor membrane permeability which limits passive diffusion.
combines with an oppositely charged ion to form a neutral complex diffuse more easily thus enhancing absorption.
What are some Drug Interactions in GIT?
Explain the example with grapefruit juice and dextromethorphan.
Flavonoids (naringin and bergamottin) in grapefruit juice inhibit P-gp (efflux transporter) and CYP3A enzymes.
This increases bioavailability of dextromethorphan which can enhance results/cause toxicity
Grapefruit juice affects drug transport in the intestinal wall.
because it is substrate for both the efflux transporters and CYP3A enzymes
Explain how PPIs cause drug interactions in GIT.
Esomeprazole & Omeprazole (PPIs) reduce gastric acid, leading to an increased gastric pH.
Drugs that require acidic conditions for absorption (e.g., ketoconazole, iron salts) will have decreased absorption in a higher pH environment.
Potential Clinical Issue: Reduced effectiveness of these drugs in patients taking PPIs.
What are the GIT challenges that oral dosage forms must be designed to overcome?
- Withstand extreme pH changes
- Presence or absence of food
- Protection Against Degradative enzymes
- Addressing Varying drug permeability in different regions of the intestine
- Overcoming GIT Motility Variability
Normal physiology processes of the GIT is affected by:
- Diet
- GIT contents
- Hormones
- Visceral nervous system
- Disease
- Drugs/drug formulation properties
What is the The enteral system?
refers to GIT from the mouth to the anus and is responsible for processing and absorbing nutrients and drugs.
What are the Major physiologic processes in the GIT:
Secretion: from cell into lumen
(The transport of substances to the lumen of the alimentary canal e.g. Enzymes (saliva) and pancreatic secretions)
Digestion: The breakdown of food constituents into smaller structures
Absorption: from lumen into cell
(The transport of the constituents from the lumen to the body (blood)). mostly in the duodenum
What is Transit time?
What does it include?
Residues exit the body via feces (anus)
Total transit time = 0.4 to 5 days
Includes
Gastric emptying
Small intestinal transit (3-4 hours healthy
Colonic transit
How does Fluid along the alimentary canal differ and affect absorption?
Relate to small intestine and colon
Small intestines has digestive juices and liquids so it is most favorable environment for drug absorption
Colon: fluid reabsorbed, hence area less moist and Lack of solubilizing effect of the chyme and digestive fluid makes it les favorable
Parts of the Enteral System
Oral Cavity
Esophagus
Stomach
Duodenum
Jejunum
Ileum
Colon
Rectum
Role of the Oral Cavity In drug absorption
mainly secretes saliva pH = 7, 1500mL secreted per day, contents: ptyalin (salivary amylase)
also secretes Mucin (glycoprotein), lubricates food and interact with drugs
Used for buccal absorption of lipid-soluble drugs
oral disintegrating tablets and sublingual take advantage of the salivary environment to deliver drugs rapidly and effectively.
Role of the Esophagus in Drug absorption
Connects the pharynx and the cardiac orifice of the stomach. Lower part ends with esophageal sphincter
Fluid pH: 5-6
Very little drug dissolution occurs in this area
Role of the Duodenum in drug absorption
Common duct from pancreas and gallbladder empties into duodenum
pH 6 - 6.5
pancreatic juices from bile duct has enzymes
Trypsin, chymotrypsin and carboxypeptidase: hydrolysis of proteins to AA
Amylase: digestion of CHOs
Pancreatic lipase: hydrolyzes fats and fatty acids
Is a site of passive diffusion due to high surface area (microvilli) and blood flow.
Food and Water Effect on Aspirin’s BA
Food and Water Effect on Erythromycin’s BA
Effect of Food on Serum Griseofulvin
BA is highest when aspirin is taken fasting with 250 ml of water
BA is highest when erythromycin is taken fasting with 250 ml of water
BA is highest when griseofulvin is taken with high fat meal
What are the parameters of bioavailability ?
Area under the curve and C max
Examples of drugs that have a decreased BA with food
Doxycycline hyclate delayed release tablets
Atorvastatin calcium tablets
Clopidogrel bisulfate tablets
Examples of drugs that have an increased BA with food
Oxycodone HCl CR Tablets
Metaxalone Tablets
Spironolactone
Examples of drugs that have little effect on BA when taken with food
Gabapentin capsules
Tramadol HCl Tablets
Digoxin Tablets
Bupropion HCI ER tablets
Absolute oral Bioavailability (F)
(F) = Fa * Fg * Fh
Factors that determine Absolute oral Bioavailability (F)
- Drug’s solubility and permeability (extent)
- Fraction of dose escaping intestine and liver extraction/metabolism is Fg and Fh respectively
Fa = extent to which drug gets absorbed
What is Presystemic metabolism?
Presystemic metabolism, also known as first-pass metabolism, refers to the metabolism of a drug that occurs before it reaches the systemic circulation. This primarily involves the liver and, to a lesser extent, the intestine, which play key roles in inactivating or transforming drugs into their metabolites before they are distributed throughout the body.
Explain the Rule of Five
This rule predicts that poor drug absorption or permeation is more likely when:
There are more than five hydrogen-bond donors
There are more than 10 H-bond acceptors
The molecular weight is greater than 500 Da
The calculated log P (ClogP)2 is greater than 5 (or Mlog P>4,15)
What are the Methods for Studying Factors That Affect Drug Absorption
- Biorelevant Drug Dissolution Studies (drug release
- Gamma Scintigraphy (site of drug release)
- Markers to study effect of gastric and GI transit time
Describe the Effect of Food on GI Drug Absorption
Intestinal pH and solubility of drugs are affected by digested food contents (amino acids, fatty acids, other nutrients
What is gastric emptying ?
What is its importance in drug absorption?
Gastric emptying refers to the process by which food, liquids, and medications move from the stomach into the small intestine for further digestion and absorption. It is a key factor in drug absorption because it determines how quickly a drug reaches the intestine, where most absorption occurs.
What is Splanchnic Blood Flow?
The splanchnic circulation supplies blood to the stomach, intestines, liver, pancreas, and spleen.
What is Luminal Metabolism?
Luminal metabolism refers to the enzymatic breakdown of drugs in the gastrointestinal (GI) tract before they are absorbed.
What is Dose Dumping?
Dose dumping refers to the rapid release of a drug from a slow-release or controlled-release formulation before it reaches the site where it’s meant to be absorbed (e.g., the small intestine).
This can occur due to a change in environmental conditions (e.g., food, alcohol, or changes in gastric pH) or due to malfunctions in the formulation (e.g., inappropriately damaged or compromised coating).
What are the Factors Affecting Drug Absorption in the GIT?
- Gastrointestinal Motility
- Gastric emptying time
- Intestinal motility
- Perfusion of GIT
- Absorption through the lymphatic system
- Effect of food
- Presystemic metabolism in intestine and liver
Drugs absorbed by passive diffusion from all parts of the alimentary canal, especially the duodenum
T/F
T
How does Gastrointestinal Motility Affect Drug Absorption in the GIT?
What are the factors affecting transit time?
(Factors Affecting Drug Absorption in the GIT)
This moves the drug through alimentary canal; hence, drug may not remain at absorption site
Transit time depends on physiochemical and pharmacologic properties of the drug, Type of dosage form and various physiologic factors e.g Fasted or fed?
Is GI motility influenced by interdigestive and digestive states?
How and what do they influence?
Gastrointestinal motility is influenced by whether the body is in the fasted (interdigestive) or fed (digestive) state.
These states determine the movement of food and drugs through the alimentary canal and significantly impact drug absorption.
Describe the Motility Pattern in the Interdigestive (Fasted) State
This cycle consists of:
Phase I: A quiet phase with little to no contraction.
Phase II: A period of intermittent contractions, signaling that the stomach and small intestine are in a transition state.
Phase III: A strong, coordinated contraction (also called the “housekeeper wave”) that sweeps any residual food or secretions from the stomach and small intestine into the large intestine. This phase is often most relevant for drug transit and gastric emptying.
Phase IV: A brief transition phase leading back into Phase I.
Describe the Motility Pattern in the Digestive (Fed) State
Contractions in the stomach that mix the food with gastric juices (creating chyme).
Slower gastric emptying into the small intestine.
Increased gastric motility to ensure digestion of food particles and absorption in the small intestine.
Reduced migrating motor complex activity, as the digestive system is focused on handling the meal.
How does delay in Gastric Emptying Time affect drugs like penicillin and aspirin?
(Factors Affecting Drug Absorption in the GIT)
Delay in gastric emptying of the drug will delay the rate and maybe the extent of drug absorption – result in longer onset time
Penicillin unstable in acid, delay in emptying can degrade the drug in the stomach
Aspirin – delay in gastric emptying can result in gastric irritation – prolonged contact
Factors That Affect Gastric Emptying Time
Consumption of meals high in fat
Cold beverages
Anticholinergic drugs
Large particles (incl tabs) delayed from emptying for 3-6 hours by the presence of food in the stomach
Indigestible solids empty very slowly
Intestinal Motility
(Factors Affecting Drug Absorption in the GIT)
Normal peristaltic movement mixes the contents in duodenum
Drug must have a sufficient time at absorption site for optimum absorption (residence time)
Disease e.g diarrhea affects
MR/CR dosage forms
Transit time (mouth to anus) is 53.3 hours measured using radio-opaque markers
Perfusion of the GIT
(Factors Affecting Drug Absorption in the GIT)
The duodenum and peritoneum are highly vascularized.
Splanchnic circulation receives ~28% of cardiac output, and increases after meals to support digestion and absorption.
High perfusion maintains a strong concentration gradient, enhancing passive diffusion of drugs into the bloodstream.
Decrease in mesenteric blood flow due to CHF, decreases rate of drug removal from intestinal tract – resulting in decreased rate of drug bioavailability
Absorption through the lymphatic System
(Factors Affecting Drug Absorption in the GIT)
This is an alternative pathway that bypasses first pass metabolism
especially for lipophilic drugs
Lipophilic drugs may be absorbed through lacteal or lymphatic vessels under the microvilli
This is because Lymphatic vessels drain into the vena cava rather than the hepatic-portal vein
What is stomach distention?
Swelling
What is antral milling?
Antral milling – process of breaking down large particles
What are the factors that Stimulating Acid Secretion (Decreasing pH)
cephalic and gastric Digestion phase
Foods high in protein
Tea. coffee, milk, alcohol
What are the factors that Inhibit Acid Secretion (increasing pH)
Intestinal Digestion phase
Foods high in fats and carbohydrates
Drugs like Histamine receptor antagonists and PPIs
Conditions like Achlohydria
How does an increase in stomach acid pH affect enteric coated tablets?
premature dissolution of enteric-coated formulations in the stomach, leading to:
Loss of protection
irritation
release at the wrong site
reduce bioavailability
How does an increase in stomach acid pH affect fat soluble acid stable drugs
fewer may be absorbed from the stomach (passive diffusion)
In which state fasting or fed is alcohol more rapidly absorbed.
Does this relate to a higher or lower acidic pH
Ethanol rapidly absorbed, in the fasting state compared to fed, in the stomach
Fasting state is more acidic
Role of the Jejunum in drug absorption
Middle portion of small intestine (between duodenum and ileum)
Digestion of protein and CHOs after adding pancreatic juice and bile
Fewer contractions than duodenum
This portion preferred for in vivo drug absorption studies
CHOs
Carbohydrates
Role of the Ileum in drug absorption
Terminal part of small intestines
Fewer contractions than the duodenum
Perfused for drug absorption studies
pH; 7 (distal part pH = 8)
Acid drugs dissolve in ileum (bicarbonate secretion present)
Bile secretion helps dissolve fats and hydrophobic drugs
Role of the colon in drug absorption
pH:5.5 – 7
Lacks villi: Low SA
Limited drug absorption: low SA, lacks blood flow; lacks the more viscous and semisolid nature of the lumen contents
Lined with mucin that functions as lubricant and protectant
Drugs dissolved in this area good candidates for oral sustained release dosage forms
Aerobic and anaerobic microorganisms: may metabolize some drugs
Mesalamine acts locally in this area in Crohn’s disease
What is Crohn’s disease
Crohn’s disease is a type of inflammatory bowel disease (IBD) that causes chronic inflammation of the gastrointestinal (GI) tract. It can affect any part of the GI tract, from the mouth to the anus, but it most commonly affects the ileum (the last part of the small intestine) and the colon (large intestine).
What is Mesalamine
Mesalamine (also known as 5-aminosalicylic acid or 5-ASA) is a medication primarily used to treat inflammatory bowel diseases (IBD), such as ulcerative colitis and Crohn’s disease. It is an anti-inflammatory drug that acts directly on the gastrointestinal (GI) tract.
Role of the rectum in drug absorption
Length:15cm
End at anus
In absence of fecal material: limited fluid (2mL)
No buffer capacity: dissolving drug/excipient can have an effect on the pH
pH: 7
Perfused by superior, middle and inferior (closest to the anal sphincter) hemorrhoidal veins
Avoids hepatic first pass effect
Absorption depends on position of suppository
