Tissue distribution

Question 1

How is tissue binding measured?

Answer 1

Rarely measured directly – inferred from plasma data

• Characterised by tissue-to-plasma partition coefficient (Kp)

Question 2

Role of hepatic uptake and efflux transporters in drug disposition:

Answer 2

A. Mediate active uptake of drugs into the hepatocyte
- e.g., uptake of atorvastatin by OATP1B1 transporter
Can result in C liver&raquo_space; C plasma

B. Excretion of drug into the bile – efflux transporters
- e.g. excretion of rosuvastatin by BCRP

Question 3

Importance of tissue distribution of drugs:

Answer 3

• Binding to tissue components and involvement of transporters (uptake or efflux) determine tissue distribution
• Knowledge of drug partitioning in certain tissues is important to estimate V in drug development

Question 4

Kp can be determined:

Answer 4

• in vitro – using tissue homogenate or isolated perfused organs
• in silico – predictive equations based on physicochemical properties of the drug and tissue composition1

Question 5

Physiologically-based pharmacokinetic (PBPK) modelling and application

Answer 5

• Mathematical description of ADME processes
• Whole body represented as a multi-compartment of individual organ compartments
• Organ compartments connected by blood flows in a physiologically meaningful way
• Physiological parameters
• Drug specific parameters

Question 6

Application of PBPK modelling

Answer 6

• Increasingly used as a decision-making tool at all phases of drug development
• Implemented in custom built or commercial software platforms
• Consideration of variability (demographic, physiological and/or genetic variability) - creation of virtual subjects
• Most commonly used to predict drug-drug interaction risk and to inform adequate design of clinical trials
• Allows prediction of PK in patients by accounting for known modifications in physiology due to disease