Week 4 - Tissue Distribution of Drugs

Question 1

What is the role of drug binding to tissue components

Answer 1

• drug in tissue can be bound or unbound (reversible process)
• ## can be used to estimate V in drug development (loading dose)

Question 2

What is the impact of drug binding to tissue components on drug distribution

Answer 2

• V is determined by relative balance of drug binding in plasma compared to tissues
• if fraction of unbound drug (fuT) is > 1 = have greater vol. of distribution (V)
• fuT is low = extensive drug binding to tissue
• drugs with large vol. of distribution binds extensively to tissue components

Question 3

What is the role of drug transporters on distribution

Answer 3

1. SLC Transporters (uptake)
   - ↑ conc. in tissue (uptake from plasma to tissue)
   - e.g. OATP (OATP1B1 and OATP1B3)
   - statins transported (uptake) into hepatocytes via OATP1B1
   OATP1B1:
   - mediates uptake of therapeutic drugs into hepatocytes
   - mediates uptake of bile acids, bilirubin
   - many drugs transported by this
   OATP1B3:
   - substrates are similar to OATP1B1 (into hepatocytes)
2. ABC Transporters (efflux)
   - movement of drug from tissue to outside of the cell (plasma)
   - ↓ unbound drug conc. in tissue
   - hepatic transporters mediate excretion of drug into bile (BCRP)

Question 4

What is the role of drug transporters in drug safety / efficacy

Answer 4

SLC Transporter - OATP1B1 (uptake)
- has many clinically relevant DDIs = transporter is investigated in many drug developments
- co-administration with inhibitor = ↓ uptake of victim drug + ↑ plasma conc. of the ‘victim’ drug = ↑ risk of adverse events ion of statins can cause muscle pain if distributed to muscle instead of liver
- e.g. accumula
- expression varies in individuals i.e. ethnicities, having variant other than wild type = ↓ activity of transporter
= less drug moving from blood to hepatocytes = ↑ conc. in plasma

Question 5

What is sub cellular drug distribution

Answer 5

1. Have cystol (containing lysosome)
   - lysosome = antibody drug conjugate, slightly acidic
2. Amine diffuses into systole (passive diffusion)
3. Amine diffuses across membrane into lysosome
   - acidic conditions ionise amine (into NH3+ from NH2)
4. Ionised form = less permeable = trapped in lysosome (can’t diffuse out across membrane into cystol)

RESULT: accumulates in lysosome
- effects MAY be positive if target is lysosme
- if target is NOT lysosome = reduced therapeutic effect + side effects
- can cause safety issues (↑ accumulation of phospholipids = phospholipidosis)

Question 6

What in silico tools are used to predict drug distribution

Answer 6

in silico = predictive equations based on physicochemical properties of the drug + tissue composition

PBPK Model
- can predict drug plasma + tissue concenttation-time profile