W2.2_ADME

Question 1

Define ADME. Define elimination, disposition, and liberation. Explain the clinical endpoints in pharmacokinetics and the important terms in a pharmacokinetics profile.

Answer 1

• Absorption: how drug gets into systemic blood from its formulation at administered site (movement into body)
• Distribution: reversible transfer of drug between blood and other tissues (movement around body)
• Metabolism: biotransformation of drug into another chemical species
• Excretion: irreversible loss of drug from systemic blood (movement out of body)
  *Elimination: M+E, irreversible loss of drug from site of measurement
  *Disposition: D+M+E
  *Liberation: before A, release of drug from its dosage form
• Pharmacokinetics: what the body does to the drug
• Clinical endpoints/metrics: measurement of drug amount/concentration in biological spaces and fluids (plasma) at specific time
• Terms: absorption lag time, Cmax, Tmax, elimination half-life

Question 2

Describe the absorption processes and properties in different routes of drug administration, including subcutaneous injection, intramuscular injection, intravenous injection/infusion, oral, and transdermal patch.

Answer 2

Subcutaneous injection
- Low blood flow: slow absorption (via diffusion/permeation through capillary wall/lymphatic system
- Used for large molecules/biologic drugs
- Molecular weight <16kDa mainly through capillary wall, >16kDa mainly to lymphatic system
Intramuscular injection
- High blood flow: fast absorption (via diffusion/permeation through capillary wall)
- Used for large molecules/biologic drugs
Intravenous injection/infusion
- Direct to vein: direct to systemic circulation
Oral
- Through GI tract, absorbed to systemic circulation usually via small intestine and hepatic portal vein
- Common for small molecule drugs
- Properties: lipophilicity, ionisation, molecular weight, solubility, permeability, formulation (excipients, enteric coating, controlled release, particle size)
Transdermal patch
- Absorption requires permeation across/into outer epidermis (stratum corneum)
- Patch can incorporate chemical/physical methods to enhance drug penetration/permeation (ex. hydration of stratum corneum)

Question 3

Explain the importance of distribution of drug molecules. Give out examples of highly/poorly perfused tissues. Describe the process of drug distribution.

Answer 3

• Determines drug concentration in blood plasma/tissues
• Different drugs have different effects in different tissues
• Highly perfused tissues: lungs, kidneys, liver, brain
• Poorly perfused tissues: muscle, skin, adipose
• Absorption -> distribute via circulatory system throughout body/tissues/organs
• Drug-binding plasma proteins (ex. albumin, α1-acid glycoprotein) binds to drug molecules -> bound drug are too large to be permeable through capillary walls -> only free/unbound drugs can reach target site and be pharmacologically active

Question 4

Briefly explain the generalised chemical equation in metabolism and the organs involved. Explain the range of metabolism pathways and the factors in variable drug response within individuals (9).

Answer 4

• Reactants: parent drug/prodrug/substrate/cofactor
• Products: metabolite/product
• Involves enzyme-mediated chemical reactions (mostly in liver, can occur in brain/lung/kidney/ blood too)
• Liver and small intestine are involved in first-pass metabolism (before systemic circulation)
• Wide variety of enzymes -> different metabolism pathways
• Variability in drug response: pregnancy, age, gender, polymorphisms, organ transplant, liver and kidney diseases, drug-drug and drug-food interactions, inflammatory mediators, diabetes mellitus

Question 5

State and explain the major and minor routes of drug excretion (3/3).

Answer 5

• Urine (through kidneys)
• Lungs (through passive diffusion), excretion of volatile substances such as alcohol
• Breast milk (through passive diffusion), have to consider both patient and infant
• Others: bile, saliva, sweat