W4 L2 - Drug absorption and bioavailability Flashcards
Absorption definition
- Movement of the drug from the site of administration into the blood (or lymph), usually across a membrane
- All processes, from the site of administration to the site of measurement
Important drug specific properties for determining route of administration:
Molecular weight
Lipophilicity
Ionisation at relevant pH
Solubility
Permeability
Route of elimination
Active transport
Important formulation specific properties to enable the selected route of administration:
Release from formulation
Solubilising components
Reminder of gastrointestinal tract anatomy and physiology
Function of GI tract:
Digestion: food is broken down into components simple enough to be absorbed in the intestine
Absorption: uptake of products of digestion by intestinal cells (enterocytes) from the gut lumen and their delivery to blood or lymph
Definition of terms: Bioavailability
- Bioavailability (F): the extent of absorption of intact drug. Fraction of an extravascularly administered dose reaching the systemic circulation intact
F - has value between 0 and 1, or is expressed in % - Absolute bioavailability: usually assessed with reference to an intravenous dose
- Relative bioavailability: Comparison of the bioavailability between formulations of a drug given either by the same or different routes of administration
Why is bioavailability important?
- Fraction of an extravascularly administered dose reaching the systemic circulation intact
- Drug concentration in blood plasma and site of action needs to be high enough to have pharmacological response
Advantages and limitations of intravenous vs. oral administration
Gold standard for comparing other routes
Absorption of the drug is complete
Can be invasive for the patient
Advantages and limitations of intravenous vs. oral administration
Convenient, most frequent, generally safe
Extent of drug reaching systemic circulation can be reduced due to first-pass effect or inappropriate drug formulation
Onset of effect can be slow
Potential barriers for oral bioavailability
- Disintegration time and dissolution rate [liberation]
Solubility and precipitation - Gastric emptying and intestinal transit
- Passive and active movement of drug across the membrane of the intestinal wall
- First-pass metabolism in intestine and liver
Oral drug bioavailability (Foral)
✅ Some of the drug is lost in the gut due to metabolism and fecal excretion.
✅ Some of the drug is lost in the liver before reaching the bloodstream.
✅ The amount of drug that actually enters the bloodstream is the oral bioavailability (F_oral).
This explains why some drugs need higher doses when taken orally compared to injections, as a portion is lost before reaching circulation.
Disintegration and dissolution
Formulation properties that affect it:
- excipients
- enteric coating
Physiology:
Stomach vs intestine
pH
Bile
Fasted vs Fed
Gastric emptying
GI Motility
How does bile enhance drug solubility?
Bile acids form micelles
Lipophilic drug preferentially distributes into lipid core of micelle
Bile acts as a natural surfactant
Food effects: Role of bile in enhancing solubility
Bile enhances solubility by acting as an emulsifier. It contains bile salts, which have both hydrophilic (water-attracting) and hydrophobic (fat-attracting) parts. These bile salts surround fat-soluble drugs and lipids, forming micelles that increase their solubility in water, aiding absorption in the intestines.
Transcellular movement of drug across the intestinal wall
- Intestine anatomy yields large surface area
- Passive diffusion, active transport or facilitated transport
Follows concentration gradient
Transport continues until equilibrium is reached - Passive diffusion, active transport or facilitated transport
Transcellular transport dependent on:
lipophilicity of the drug
molecular size - size, permeability
degree of ionisation
surface area available – varies along the gut
Slow movement for large, polar and more charged molecules
Importance of drug properties: Lipinski’s rule of five
An orally administered drug should not violate more than one of the four following criteria:
- No more than 5 hydrogen bond donors
- No more than 10 hydrogen bond acceptors
- Molecular weight less than 500 g/mol
- LogP not greater than 5
- First-pass metabolism
- Loss of a drug as it passes through intestine and liver during absorption (pre-systemic metabolism)
- Metabolism predominantly occurring via CYP3A4 (Cytochrome P450 3A4 - metabolic enzyme)
- Extensive first pass metabolism will reduce the bioavailability of a drug
- First-pass metabolism
This slide explains first-pass metabolism, where a drug taken orally is metabolized before reaching systemic circulation.
Key Points:
Hepatic Blood Flow: The liver receives blood from both the hepatic artery (oxygen-rich) and the hepatic portal vein (nutrient-rich from the intestines).
Drug Absorption: After ingestion, 100% of the dose enters the stomach and intestines.
Metabolism Before Circulation:
Gut enzymes (CYPs, Phase I & II) metabolize part of the drug.
The remaining drug enters the portal vein, reaching the liver.
Liver enzymes (CYPs, Phase I & II) further metabolize the drug.
Only a fraction (e.g., 15%) reaches systemic circulation.
Conclusion:
First-pass metabolism reduces the amount of drug that reaches the bloodstream, affecting its overall effectiveness.
what are phase I
Phase I Enzymes (Modification Reactions)
Function: Introduce or expose functional groups (e.g., -OH, -NH2) to make the drug more water-soluble or prepare it for Phase II.
Reactions: Oxidation, reduction, hydrolysis.
what are phase 2 enzymes
Phase II Enzymes (Conjugation Reactions)
Function: Attach water-soluble molecules (e.g., glucuronic acid, sulfate) to the drug for easier excretion.
Reactions: Glucuronidation, sulfation, acetylation, methylation, glutathione conjugation.
Sources of inter-individual variability in drug absorption and bioavailability
- Diet (fed, fasted, high fat, paediatric, hydration)
- Other drugs (PPIs)
- Age (paediatric)
- Disease/ disorders
Hypochlorhydria
Eating disorders
Gastric bypass surgery
Coeliac disease
Factors affecting drug metabolising enzymes
- age
- gender
- polymorphisms
- organ transplant
- liver diseases
- kidney diseases
- drug-drug interactions
- inflammatory mediators
- diabetes Miletus
- pregnancy
Factors affecting drug dissolution in GI tract
- pH
- fluid volume/contents
- transit time
- bile
Factors affecting permeation
- pH
- SA of intestine
- Transit time
Altered absorption due to GI physiology
- due to det obesity, people need surgeries such as gastric bypass
Effects of gastric bypass surgery on drug absorption: - Large physiological changes - reduction in surface area of stomach, pH changes
- Bypass of main areas of drug absorption – e.g., duodenum and the jejunum (~75cm bypassed)
- Gastric bypass surgery reduces absorption for many drugs, particularly those with low solubility or permeability, which may require dose adjustments.
