Absorption

Question 1

What is ADME (4)

Answer 1

1. Absorption
2. Distribution
3. Metabolism - chemical conversion
4. Excretion - removal of unchanged chemical

Question 2

What are the routes of entry for drugs (8)

Answer 2

1. Oral
2. Inhalation
3. Dermal
4. Injection
5. Infusion
6. Eye drops
7. ear drops
8. nasal sprays etc

Question 3

What are the routes of entry for cosmetics (3)

Answer 3

1. Dermal
2. Inhalation
3. Oral

Question 4

What is the paracellular route (2)

Answer 4

1. Passive diffusion between cells; hydrophilic compounds e.g. Levothyroxine
2. Experimental agents to modify pore diameter to absorption

Question 5

What is the transcellular route: passive diffusion (5)

Answer 5

1. The most common mechanism for the oral route
2. Compound moves from high to low concentration (Fick’s law)
3. requires an appropriate balance of lipid & aqueous solubility
4. Driven by the concentration gradient and lipid solubility
5. (most drugs have adequate aqueous solubility)

Question 6

What is passive diffusion efficient for (6)

Answer 6

1. Most drugs
2. Anaesthetics
3. Alcohols
4. Lipids
5. Hydrocarbons
6. Passive diffusion is non-specific - chemicals need suitable solubility

Question 7

What is passive diffusion inefficient for (4)

Answer 7

1. Carbohydrates
2. Proteins
3. Ionised molecules
4. Large molecules

Question 8

What is the transcellular route: facilitated diffusion (3)

Answer 8

1. Diffusion from area of high low concentration using specific transmembrane proteins (does not require ATP; saturable)
2. Structurally selective gateway for specific compounds
3. Binds to transporter which undergoes conformational change & release compound on opposite side

Question 9

What is the transcellular route: active transport (3)

Answer 9

1. Can move against a concentration gradient
2. requires ATP; saturable
3. Structurally selective gateway for specific compounds

Question 10

What is structurally selective uptake (3)

Answer 10

1. Chemicals undergo facilitated diffusion or active transport only when they fit an endogenous transporter
2. Solute Carrier (SLC) and ATP-Binding Cassette (ABC) transporters
3. applies to few chemicals although an increasing number of transporters now identified (>400) therefore more possibilities

Question 11

What are the 3 transporters and their locations (3)

Answer 11

1. Large Neutral Amino Acid Transporter (LAT1) - Blood-Brain Barrier
2. Organic Anion Transporter (OAT) - Brain; kidneys; placenta etc
3. Organic Cation Transporter (OCT) - Liver; small intestine

Question 12

What are efflux transporters (P-gP) (3)

Answer 12

1. After absorption substrates for efflux transporters may be ‘pumped’ back out of the cell & returned to the gut lumen
2. Similar occurs in the liver where chemicals are “represented” to metabolising enzymes*
3. Transporters, together with enzymes, are a protective mechanism

Question 13

What is P-gP (2)

Answer 13

1. P-gP (permeability glycoprotein – protein with carbohydrates)
2. Also known as multi-drug resistance protein 1 (MDR-1) a member of the ATP Binding cassette family of transporters

Question 14

What are the locations and functions of P-gP (5)

Answer 14

1. Intestine - Prevents chemical uptake into the system
2. Liver - Excretion to bile / re-presents chemical to metabolising enzymes
3. Kidney - Excretion into urine
4. Brain - Prevents uptake into the brain
5. Tumours- Prevents uptake of chemotherapeutic agents – drug-resistant tumours

Question 15

What is the effect of administering a P-gp substrate (2)

Answer 15

1. Reduced intestinal absorption
2. Resistance to chemotherapy

Question 16

What is the effect of administering a P-gp inductor

Answer 16

Reduced absorption of co-administered drugs

Question 17

What is the effect of administering a P-gp inhibitor

Answer 17

Saturates P-gP, increases absorption of co-administered drugs (therapeutic potential)

Question 18

What is the rate and extent of absorption (7)

Answer 18

1. A rate constant links the rate of an ADME process to the amount of chemical **or drug available to undergo the process
2. Assumed to be “First Order” i.e. the rate of the process is directly proportional to the amount of drug available for the process
3. Rate = Rate Constant x Mass of Drug
4. In the case of absorption: Rate of absorption = Ka x Mass of drug awaiting absorption
5. NB: Ka is the absorption rate constant written as Ka or Kabs
6. The drug may be awaiting absorption from the gut or a sub-cutaneous or intra-muscular depot
7. For some drugs, equal amounts are absorbed over a given period irrespective of the amount available for absorption

Question 19

What are the factors affecting Ka (4)

Answer 19

1. Each drug has its own absorption rate depending on its properties (some are rapidly absorbed, others slower) (e.g. digoxin has slow absorption due to high water solubility)
2. Drug formulations can be adjusted to give different rates of absorption for the same drug (e.g. slow release formulations will slow absorption)
3. Inter-patient variability
4. Intra-patient variability (e.g. eating a large/fatty meal may slow the movement of the drug to the intestine, slowing absorption)

Question 20

What is HIA

Answer 20

Human Intestinal Absorption (HIA) is the percentage of drugs that is absorbed from the gut into the bloodstream.

Question 21

What is bioavailability (2)

Answer 21

1. Bioavailability (F) is the fraction of unchanged drug that reaches the systemic blood circulation
2. i.e. for an orally administered drug to have good bioavailability, it must be well-absorbed and avoid “first-pass” metabolism

Question 22

How is bioavailability written (4)

Answer 22

1. If F = 100% (may be written as F = 1), then all of the dose reaches the systemic circulation
2. If F = 25% (may be written as F = 0.25), then one-quarter of the dose reaches the systemic circulation.
3. F ranges from 0 – 100% (or 0 – 1) and has no units
4. If a drug is given i.v. then by definition F = 100%

Question 23

How is Oral bioavailability calculated (2)

Answer 23

1. The drug in the patient’s systemic circulation = Dose x F
2. F = (AUC 𝑜𝑟𝑎𝑙 𝑟𝑜𝑢𝑡𝑒)/(AUC 𝑖.𝑣. 𝑟𝑜𝑢𝑡𝑒)

Question 24

How does drug metabolism affect bioavailability (5)

Answer 24

1. Drug metabolising enzymes are found in most tissues; Liver and gut contain high levels of enzymes
2. CYP 3A4, CYP 2D6 & CYP 2C9 most relevant for drugs
3. Enzymes may be induced or inhibited by other drugs, foods, herbal remedies, etc; this will alter the bioavailability of drugs metabolised by these enzymes
4. Low bioavailability (F) is problematic as inter-individual variability leads to large discrepancies between patients in terms of circulating doses
5. The majority of drugs have been engineered to have high F

Question 25

What is the salt factor (5)

Answer 25

1. Drugs may be administered as salts to increase solubility, but the mass of the parent drug defines doses.
2. Therefore, we need to adjust the dose given to take into account the “salt factor”
3. Dose of salt form of drug = (Dose of Drug Required)/(Salt Factor)
4. For example, theophylline is generally administered as aminophylline, which contains 80% w/w theophylline. Hence, the salt factor = 0.8
5. If we wish to administer 400mg of theophylline, we would require: Dose of the salt form (aminophylline) = (400 mg)/0.8 = 500mg aminophylline.