(1A) - Distribution Concepts and Protein Binding

1-compartment model

• Drug distributes:

• Instantaneously

• Uniformly

• Complete

Real body ≠

 uniform → distribution is complex

Volume of Distribution (Vd)

• Defined as:

“Apparent space drug distributes into”

Volume of Distribution (Vd)

 IMPORTANT:

• NOT a real physical space

• Just a mathematical value

Even if Vd ≈ body fluid → does NOT mean

• drug only goes there

• Example:

  • Lipophilic drug → prefers fat

  • Hydrophilic drug → stays in plasma

DISTRIBUTION STARTS WITH…

BLOOD

Blood Components:

• Plasma proteins

• Red blood cells

Extravascular Tissues:

• Proteins

• Fat

• Bone

States of Drug in blood

• Free drug

• Bound drug

Only FREE drug can:

• Be absorbed

• Distribute

• Be metabolized

• Be excreted

• Produce pharmacologic effect

Free drug =

ACTIVE drug

BOUND DRUG

• Attached to proteins/macromolecules

• Cannot:

  • Cross membranes

  • Be metabolized

  • Be excreted

  • Produce effect

BOUND DRUG

think…

inactive storage

Protein Binding

• Drug + macromolecule interaction

 

Types of Binding - overview

Reversible (MOST COMMON)

Irreversible

Reversible (MOST COMMON)

• Weak (H-bond, Van der Waals)

• Drug can bind/unbind

 Irreversible

• Covalent bonding

• Permanent

🚨 Example:

• Acetaminophen toxicity → liver damage

  • Reactive metabolite binds liver proteins → damage

Factors Affecting Binding

1. Drug Factors

• Molecular weight

• Lipophilicity

• Drug concentration

 

2. Protein Factors

• Amount of protein

• Type/structure

 

3. Drug–Protein Affinity

• Strength of binding

 

4. Drug Interactions

• Compete for same binding site

• Can increase free drug → toxicity

 

5. Patient Conditions

• Liver disease ↓ proteins

• Uremia alters binding

• High drug + low protein →

• Low drug + high protein →

• High drug + low protein → MORE free drug

• Low drug + high protein → MORE bound drug

MAJOR PROTEINS - overview

1. ALBUMIN

2. α1-ACID GLYCOPROTEIN

3. LIPOPROTEINS (LDL, HDL)

4. ERYTHROCYTES (RBCs)

5. OTHER

   1. IV TUBING / IV SET BINDING

   2. TPN (TOTAL PARENTERAL NUTRITION) INTERACTIONS

 ALBUMIN

• Most abundant protein

• Produced by liver

• Long half-life (~2–3 weeks) (t½: ~17–18 days)

• Normal: 35–50 g/L

ALBUMIN

function

• Maintains osmotic pressure in the blood

• Transports poorly soluble substances

ALBUMIN

Binds:

• Acidic drugs

• Hydrophobic drugs

ALBUMIN

Key Features:

• Multiple binding sites

• Can bind strongly

ALBUMIN

CLINICAL PEARL

• Liver disease → ↓ albumin → ↑ free drug

 α1-ACID GLYCOPROTEIN

• Lower concentration (0.4–1.0 g/L)

• Produced in liver

 

 α1-ACID GLYCOPROTEIN

Binds:

Basic drugs

α1-ACID GLYCOPROTEIN

Key Features:

• Low capacity (few sites)

• High affinity

LIPOPROTEINS (LDL, HDL)

• Transport lipids

LIPOPROTEINS (LDL, HDL)

Binding Mechanism

• Drug dissolves in lipophilic core

LIPOPROTEINS (LDL, HDL)

Binds:

• Highly lipophilic drugs

LIPOPROTEINS (LDL, HDL)

function

transport corticosteroids

 ERYTHROCYTES (RBCs)

• Usually minimal binding

💡 Examples:

• Cyclosporine (~50%)

• Phenytoin (~25%)

KEY CLINICAL IDEA

Pharmacokinetics (ADME) depends on FREE drug

 Total drug ≠

active drug
→ Only free drug matters

High protein binding ≠

stronger drug
→ Actually less active (less free drug)

STEP-BY-STEP FLOW

1. Drug enters blood

2. Drug ⇄ binds to protein

3. Only free drug moves

4. Free drug:

   • Distributes

   • Gets metabolized

   • Gets excreted

   • Causes effect

IV TUBING / IV SET BINDING

Key idea:

Some drugs bind to:

• IV tubing

• Plastic/plasticizers

IV TUBING / IV SET BINDING (VERY TESTABLE CONCEPT)

a. Result:

b. solution

a. Drug never reaches patient

b. Prime IV line

• Run albumin or other solution first

• Coat tubing → prevent drug loss

TPN (TOTAL PARENTERAL NUTRITION) INTERACTIONS

Contains:

• Lipids

• Amino acids

• Carbs

TPN (TOTAL PARENTERAL NUTRITION) INTERACTIONS

Key concept:

Lipophilic drugs bind to lipids in TPN

TPN (TOTAL PARENTERAL NUTRITION) INTERACTIONS

Causes:

• Drug binding / loss

• Compatibility issues

DRUG “PROMISCUITY”

• Drugs bind to many unexpected things

• Not just proteins

• Basic drugs →

• Acidic drugs →

• Basic drugs (Hydrobromide drug) → AAG

• Acidic drugs → Albumin

FREE FRACTION (fᵤ)

Fraction of drug that is free (unbound)

FREE FRACTION (fᵤ)

equation (ON FORMULA SHEET)

Bound fraction: equation

fu and fb relation

Equation to CONVERTING BETWEEN FREE & TOTAL CONCENTRATION

Equation to CONVERTING BETWEEN BOUND & TOTAL CONCENTRATION

What is this equation about? Equation be give in exam!

(this math problem in HW)

• it used when correcting for altered plasma protien

PHENYTOIN (SPECIAL CASE)

• it’s similar to previous flashcard but with phenytoin

• ~95–98% protein bound

• Very sensitive to albumin changes

• this equation NOT on the exam