W4.3_Drug Absorption and Bioavailability

Question 1

How does drug absorption affect its formulation? Define bioavailability. Contrast absolute and relative bioavailability.

Answer 1

• Different drug specific properties -> affect release from formulation and solubilising components -> enable selected route of administration (oral drugs are processed through same anatomy/physiology as food)
• Bioavailability (F): extent of absorption of intact drug into systemic circulation (0-1, or in %)
• Absolute bioavailability: with reference to intravenous dose
• Relative bioavailability: comparison between formulations of a drug (same/different routes of administration)

Question 2

How does bioavailability impact its pharmacological response? Explain the properties of bioavailability in IV, oral doses and biological drugs.

Answer 2

• Drug concentration in blood plasma and site of action has to be high enough to have pharmacological response
• IV dose: complete absorption, but invasive
• Oral: first-pass effect and inappropriate drug formulation can reduce bioavailability, slow onset
• Proteins (monoclonal antibodies, hormones): X oral ∵ will be digested by proteolytic enzymes in stomach

Question 3

Explain the Lipinski’s rule of five.

Answer 3

• Oral administered drugs should not violate more than one of the following criteria
• ≤5 hydrogen bond donors (FON atoms that are bonded with H)
• ≤10 hydrogen bond acceptors (lone pair of electrons)
• Molecular weight <500 g/mol
• LogP ≤5

Question 4

What are the potential barriers for oral bioavailability (4)?

Answer 4

-> Disintegration time and dissolution rate (liberation)
- Drug properties (ex. pKa, lipophilicity, solubility), formulation properties (ex. excipients, enteric coating), physiology (ex. stomach/intestines, pH, bile, fasted/fed, gastric emptying, GI motility) can affect the liberation of drug
- Bile: act as surfactants, better dissolve lipophilic drugs by forming micelles from bile acids -> drug preferentially distributes into lipid core -> act as natural surfactant
-> Gastric emptying and intestinal transit
-> Passive and active movement of drug across membrane of intestinal wall
Intestines have high surface areas
- Passive diffusion: follows concentration gradient, transport continues until equilibrium reached
- Transporter-mediated: can change bioavailability, through active transport/facilitated transport (ex. P-glycoprotein)
- Transcellular transport depends on lipophilicity, molecular size, degree of ionisation, SA available (general: large/polar/charged molecules have slower movement)
-> First-pass metabolism
- Occurs in intestine and liver, predominantly through CYP3A4 class of metabolic enzymes (ex. loperamide, reduces GI intake and more elimination through bile excretion)
- Wide variety of enzymes to metabolise drugs (ex. oxidation, conjugation), split into phase I/II
- Examples of high first-pass metabolism: simvastatin, atorvastatin, lovastatin, saquinavir, felodipine, rifabutin, cyclosporine, tacrolimus, sildenafil, nisoldipine, verapamil, diltiazem

Question 5

Explain the inter-individual variability in bioavailability. What is the impact of gastric bypass surgery?

Answer 5

• Diet (fed/fasted/high fat/paediatric/hydration), other drugs (PPIs), age (paediatric), diseases (hypochlorhydria, eating disorders, gastric bypass surgery, coeliac disease)
• Gastric bypass surgery: reduce SA in stomach, pH changes + bypass parts of duodenum and jejunum -> drug exposure changes actually varies (increased/reduced/unaltered)