Tissue distribution of drugs

Intended learning outcomes:

• Understand the role of drug binding to tissue components and its impact on drug distribution
• Understand the role of drug transporters on distribution and drug safety/efficacy
• Understand subcellular drug distribution
• Understand principles of in silico tools used to predict drug distribution

Tissue distribution of drugs:

• Tissue binding is often inferred from plasma data
• At equilibrium the tissue distribution of a drug within the body depends upon binding to both plasma proteins and tissue components
• 
• The tissue- plasma partition coefficient (Kp) gives an idea of what extent drug may be potentially accumulating in the tissue

Role of transporters in ADME processes:

• For many of the new drugs, they are ionised and had poor permeability and rely on transporter proteins
• SLC - involved in uptake of drug from blood to particular tissue
• ABC - mediate efflux of drug from tissue back into systemic circulation

OATP:

• Located in membrane of hepatocytes
• Only anion drugs will be substrates for this transporter
• OATP1B1:
  • Uptake of therapeutic drugs into hepatocytes
• OATP1B3:
  • Active uptake of glutathione into hepatocytes
  • Can be expressed in some cancer tissues

Clinical relevance of OATP1B1 transporter:

• Co-administration:
  • Co administration with OATP1B1 inhibitors can lead to decrease in active uptake of drug into hepatocytes
  • This leads to an increase in plasma concentration of drugs so there is an increase in adverse effects
• Variation in expression:
• SLOC1B1 c521T>C is the most relevant snp. This leads to decreased ability of OAT1P1B1 leading to elevated blood concentration resulting in increased myopathy
• 521 CC variation leads to decreased OATP1B1 activity, reduced uptake into the liver and increased myopathy when taking statin - so concentration of statin is higher

Effect of active transport and/ or rapid metabolism in cell