tissue distribution

Question 1

what is tissue binding?

Answer 1

Rarely measured directly – inferred from plasma data. Unless you actually isolate the tissue, it is very difficult to measure the concentration of the drug. Often done in pre-clinical studies.
Multiple processes that are happening during the binding, as plasma components have different plasma proteins – molecules bind to come extent to the proteins, this is a reversible process.

Question 2

what is the equilibrium characterised by?

Answer 2

tissue-to-plasma partition coefficient (Kp)

• The simplest scenario – drug distributes between plasma and a net tissue

Question 3

what is the role of hepatic uptake and efflux transporters in drug disposition?

Answer 3

A. Mediate active uptake of drugs into the hepatocyte from the blood

• e.g., uptake of atorvastatin by OATP1B1 transporter, transports anion molecules. Most of the statins are poorly permeable to rely on transporters.
• can result in C liver&raquo_space; C plasma

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

Question 4

what is the importance of tissue distribution of drugs?

Answer 4

 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
 Kp can be determined:

Question 5

what is invitro?

Answer 5

using tissue homogenate or isolated perfused organs

Question 6

what is in silico?

Answer 6

predictive equations based on physicochemical properties of the drug and tissue composition1

Question 7

what is PBPK modelling?

Answer 7

 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 8

what is the application of PBPK modelling?

Answer 8

 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