Protein Binding & Distribution Flashcards
What is distribution?
Reversible movement of drug between the systemic circulation and the tissues of the body (ex. organs, fat, muscle)
For drugs that extensively distribute into the tissues, do they have high plasma concentrations?
No, for drugs that are extensively distributed into the tissues, most of the drug has left the systemic circulation (low Cp)
For drugs that experience limited distribution into the tissues, are they in relative high concentration in the systemic circulation?
Yes, most of the drug is in the blood (high Cp)
What is protein binding?
It is the non-covalent, reversible interaction of a drug with a protein to form a drug-protein complex
What are some examples of drug-protein interactions important to PK and PD?
- Drug-transporter complex (drug is transported across membrane)
- Drug-enzyme complex (drug is metabolized to metabolite)
- Drug-plasma protein complex (drug is bound to plasma protein)
- Drug-receptor complex (drug produces therapeutic effect)
What is the basic tenet of pharmacology?
Pharmacological response is related to the unbound drug concentration at the receptor site
Review slide 6 for movement of unbound drug in the body
Review slide 8 for the mathematical relationship describing drug-protein interactions
What are the variables that describe affinity for binding in drug-protein complexes?
Kd, Km, EC50
These variables represent concentration required to reach half-maximal capacity, therefore higher the variable value, lower affinity
What variables describe capacity for binding in drug-protein complexes?
nP, Tmax, Vmax, Emax
At saturation, as drug concentration increases, fraction of unbound increases because no more vacant receptors are left
What are some factors that influence drug-protein binding?
- Drug properties
- Protein properties
- Affinity
- Drug interactions (competitive binding)
- Pathophysiological condition
Review slide 11 for the equation that relates concentration of bound drug to concentration of unbound drug, binding capacity, dissociation constant
What is fu(b) (fraction unbound)?
This variable indicates the relationship between unbound drug plasma concentration with total plasma drug concentration
remains constant until saturation
What are the three types of plasma binding proteins?
- Albumin
- Alpha-Acid Glycoprotein (AAG)
- Cortisol Binding Globulin Lipoproteins
What are some characteristics of albumin in relation to protein binding?
Principal binding plasma protein
Acidic lipophilic drugs bind more readily and extensively than basic lipophilic drugs
Small, neutral, water-soluble drugs are negligibly bound
What are some characteristics of Alpha-Acid Glycoproteins (AAG)?
Lower concentration than albumin, but still important
Concentrations of AAG rapidly increase with inflammation (reducing unbound drug)
Binds to basic drugs
Can protein-bound drug exert a pharmacological effect?
No, only unbound drug exerts pharmacological effect
Can protein-bound drug be eliminated?
No, most elimination mechanisms require free drug
What types of drugs are we most concerned about the effects of protein binding?
Drugs that are extensively bound to plasma protein. These drugs have a unbound fraction below 0.2 (80% of drug in the plasma is bound to plasma proteins)
What factors determine the rate and extent of drug distribution?
- Tissue perfusion
- Drug permeability characteristics
- Protein binding and partitioning (Kp)
What conditions slow down approach to tissue equilibrium?
Poor perfusion
Higher tissue partitioning
What are the rate-limiting steps of distribution?
- Perfusion rate-limited
- Permeability rate-limited
What are the characteristics of a perfusion rate-limited drug distribution?
Tissue membrane presents no barrier to drug distribution (rapid equilibrium)
Small, lipophillic drugs are at risk of experiencing perfusion rate-limited distribution
Affects loosely knit membranes or porous capillaries
What are the characteristics of a permeability rate-limited drug distribution?
Membrane is a barrier to drug distribution (slow equilibrium)
Large or polar drugs are susceptible to permeability rate-limited drug distribution
Affects tight membrane barriers (BBB, blood-testes barrier, blood-milk barrier)
How can cardiovascular function affect drug distribution?
Patients with reduced CO or tissue perfusion, will result in lower drug concentration in the tissue (also equilibrium will take longer)
What factors determine extent of distribution?
- Tissue Blood Flow
- Tissue Blood Volume
- Partitioning (Ctissue/Cblood)
- Protein binding
- Apparent volume of distribution
What is apparent volume of distribution?
A measure of the extent of drug distribution (an indirect measure of tissue binding)
It is a proportionality constant relating drug concentration in blood to amount in the body (The volume of fluid that the drug appears to distribute into)
What does a large Vd (more than 0.6L/kg) reflect?
A large Vd value means more drug is in the tissue
What are the two main compartments of the body?
- Water compartment (blood, plasma, extracellular, and intracellular)
- Tissue and Fat Compartment (Nonadipose and adipose)
What are the specific factors that affect volume of distribution (Vd)?
- Variation in binding parameter (capacity and affinity)
- Competitive Binding Displacements (dependent on the combination of affinity and concentration)
- Relative pH of tissue and fluid compartments (unionized vs ionized)
- Blood flow (cardiac output)
- Barrier integrity
- Body Weight and Composition
How does variation in binding parameters (capacity and affinity) affect volume of distribution (Vd)?
There are individual differences in the number of binding proteins (capacity) and how strongly these proteins bind to drugs (affinity)
This affects unbound fraction in the blood. Any increases or decreases in fub, causes changes in Vd
How does competitive binding displacement affect volume of distribution?
Drug-Drug interaction:
Competition between two highly bound drugs for the same target (differences in affinity and concentration cause one of the drug to be less bound to plasma proteins, increasing the released drug’s unbound fraction, therefore increasing Vd)
Drug-endogenous molecule interaction:
Compounds like bilirubin have high affinity to albumin, displacing other drugs that are also highly bound. This increases the unbound fraction of the drug, increasing volume of distribution (ex. patients with Jaundice need to take different doses of drugs that are highly bound)
What are some characteristics of a displacer?
For significant displacements to occur, the displacer must have the following:
- High affinity for the protein
- Bind at the same site or affect the binding site of the displaced drug
- Be in high concentration to saturate binding capacity (limiting factor)
How does relative pH of tissue and fluid compartments affect volume of distribution (Vd)?
pH has an affect on the ratio of unionized and unbound drugs
ex. Ion trapping (breast milk is acidic, but basic drugs in the blood are not able to leave the milk, causing basic drugs to be found in the milk more often than acidic drugs)
How does blood flow affect volume of distribution (Vd)?
Cardiac output is a good measure for perfusion
Increase in Vd:
Decreases in CO can cause Vd to decrease for extensively distributed drugs because more is in the blood
Decrease in Vd:
Decreases in CO can increase Vd in drugs distributed in total body water (heart failure causes ascites, more water is in the tissues, therefore more of drug is in the tissues vs the plasma)
How does barrier integrity affect volume of distribution?
Disease states:
Loss of tissue barrier integrity allows increased penetration of drug into tissues (less drug in the fluid, therefore increased Vd)
Transporter Expression:
This can affect how much drug is pumped into cell and how much is pumped back out (this can affect apparent volume of distribution)
How does body weight and composition affect volume of distribution (Vd)?
Drug does not partition into fat:
Vd is proportional to lean body weight (water+bone+muscle)
Drug does partition into fat:
Vd is related to total body water
