Week 1 - Drug Absorption and Bioavailability Flashcards
Define absorption & its important on a drugs systemic exposure
Absorption - movement of drug from site of administration into the blood (or lymph) across a memebrsne
- vascular absorption = into blood
- lymphatic absorption = into lymph
Importance:
- a specific conc. of drug needs to be absorbed + reach it’s site of action to have therapeutic effects
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What does bioequivalence mean & how is it assessed
Formulations containing the same dose of a chemical entity , given in the same dosage form which are interchangeable
- i.e. 2 drugs classed as bioequivalent should act the same, have same therapeutic effects + side effects, can be substituted for each other etc.
Process to determine if >2 drugs are bioequivalent
1. have 2 groups and give one group the new drug + other group the reference
2. after phase 1 have washer period (allows elimination of initial drug)
3. then swap the drugs over between the groups
4. assess the effects; are products interchangeable? Can a patient switch safely between the 2?
- products are bioequivalent if their curves on Cmax-rate graph are the identical
How does drug move across intestinal epithelium
- Solid drug (oral) is swallowed and reaches GI lumen
- Drug dissolves in lumen of small intestine = disintegration + dissolution occurs = fine particles formed
- Smaller drug particles can moves across small intestine (SI) membrane
- SI have large circular folds = ↑ SA = ↑ drug absorption
- SI have villi which ↑ SA
- villi have a single layer of epithelial cells (= enterocytes)
- enterocytes have microvilli on surface = ↑ SA
- enterocytes l Royce important metabolic enzymes e.g. CYP3A - Drug reaches systemic circulation
- when drug enter CYP3A enzyme it’s metabolised = drug + it’s metabolites can reach systemic circulation
- drug that reaches systemic circulation = dose
What are the 4 rate-limiting steps for oral drug absorption
- Dissolution rate and disintegration time
- Gastric emptying + intestinal transit
- Movement across membrane
- perfusion limited or permeability limited - 1st pass metabolism in small intestines and liver
How does gastric emptying effect absorption of orally administered drugs
- Emptying controls the delivery of drug to the small intestines = absorption rate is affected
- drug moves from stomach to small intestines (SI)
Factors effecting gastric emptying:
- Co-administration of another drug
- some drugs ↑ Cmax = faster absorption and some will ↓ Cmax = drug is absorbed over longer time period
- Presence of food
- Age (i.e. elderly have delayed emptying)
Can reduce bioavailability
How does food effect drug absorption
Fasted State (just water NO food) :
- FAST delivery from stomach to small intestines
= taking drug on empty stomach has rapid onset of therapeutic effects
- quicker gastric emptying
- favourable for enteric coated drugs (acidity of stomach can damage coating)
Fed State:
- have delayed gastric emptying
- favourable for poorly soluble drugs as it increase dissolution time for the drug
= more drug can be absorbed by time drug reaches small intestine
How does disease effect drug absorption
Coeliac disease:
- expression of intestinal CYP3A is ↓ in uncontrolled coeliac
Crohn’s Disease:
- expression of CYP3A + other enzymes ↓
Liver Cirrhosis:
- effects hepatic 1st pass
- reduced activity of metabolic enzymes + transporters
Chronic kidney disease:
- prolonged gastric emptying time
Gastric bypass surgery
- can end up removing main areas of drug absorption
- can increase or decrease F
What is perfusion limited absorption
When membrane offers NO barrier to drug movement but BLOOD FLOW limits rate of absorption
- ↑ blood flow = ↑ absorption
- small, non-polar lipophilic molecules + water can easily cross membrane as membrane is permeable
- molecules move via passive diffusion
- large polar drugs = more difficult
Absorption is between blood and absorption site
What is permeability limited absorption
When membrane is a BARRIER to drug movement / drug is LOW permeability molecule
- poor / low permeability drugs won’t be able to cross membrane easily (from blood to absorption site) - e.g. large, polar, hydrophilic molecules or ions can’t pass via passive diffusion (require active transport) - changes in blood flow has NO effect on absorption rate
How does drug release (from its formulation e.g. solid) differ between Permeability rate-limited absorption and Dissolution rate-limited absorption
- Permeability rate-limited absorption
- LOW permeability molecules have RAPID dissolution
= poor permeability of drug is limiting factor - rapid dissolution = faster release from solid formulation = drug is seen in solution quicker = drug is absorbed
- absorption rate depends on solubility of drug
- LOW permeability molecules have RAPID dissolution
- Dissolution rate-limited absorption
- HIGH permeability molecules have SLOW dissolution
= drug is released slowly from formulation (= limiting factor) - occurs with MR / CR drugs (adjusted rate of release)
- affects absorption and plasma conc. of drug
- BENEFIT: dosing interval long = better adherence + compliance compared to immediate release (frequent dosing)
- HIGH permeability molecules have SLOW dissolution
Explain how movement across membrane changes in ionised and unionised form of drug
Unionised - drug is more lipophilic = can cross membrane easily
Ionised = drug is polar + more hydrophilic = harder to cross membrane
Explain how first pass metabolism affects absorption
First pass metabolism - loss of drug as it passes through small intestines + liver (during absorption process)
- drug can be lost via metabolism + excretion
- limits drug absorbed via oral administration
F = bioavailability (unchanged fraction of drug that reaches systemic circulation)
- drug which escapes metabolism in small intestine contributes to F
- will enter liver via hepatic portal vein
- CYP3A common enzyme that metabolises drugs - drug which is not eliminated / excreted by liver contributes to F (drug will reach systemic circulation)
What are the use of efflux transporters
Remove drug / metabolites from body
Inhibition of transporters contributes to DDIs and drug-food interactions
- e.g. drinking grapefruit juice inhibits CYP3A enzyme = drugs metabolised or excreted via this enzyme (statins) will accumulate in body = ↑ risk of toxicity + ADIs
- food binds to enzyme irreversibly, can only recover by synthesising new CYP3A4
What are the effects of intestinal efflux transporters (P-gp) on drug bioavailability
- Can be found on enterocytes (intestinal)
- Results in ↓ in conc. of drug and it’s metabolites (in intestinal lumen) = ↓ bioavailability
- ↑ exposure to CYP3A4 leads to ↓ bioavailability
P-glycoprotein (P-gp) mediates efflux of drug:
- from intestinal cell to interstitial lumen
- into bile (biliary secretion)
P-gp is a clinically relevant transporter which is important + needs to be considered in drug development
- inhibition of enzyme contributes to DDIs
What does bioavailability mean
Is the amount of extravascularly administered dose that reaches systemic circulation unchanged / in tact
Bioavailability = F
- has a value from 0-1 (0-100%)
Absolute bioavailability- seen with IV administered drugs
Incomplete absorption ↓F
- all of drug reaches systemic circulation
Relative bioavailability- used to compare same drug in diff. forms that are administered through the same or different routes.
Extravascularly administered:
As drug passes through liver + small intestines some may be lost due to metabolism or excretion = bioavailability affected
