Protein-binding

[Ref: SH4:p12]

Carriers

Most acidic drugs binds to albumin

Basic drugs bind to alpha1-acid glycoprotein

Importance of protein-binding

Only free (i.e. unbound) fraction is able to cross cell membrane

 

Thus,

• When protein binding is high
  --> Drugs kept in plasma
  --> Plasma concentration is high
  --> Calculated Vd is lower
• Only unbound fraction can enter hepatocytes and cross glomurulus
  --> Only unbound fraction can undergo hepatic metabolism and glomerular filtration

Changes in protein binding

Especially important for drugs which are normally highly protein-bound

Because small changes in binding
--> Large changes in free fraction

e.g. propanolol, phenytoin, diazepam

 

Determinants of protein binding

• Lipid solubility
  * Protein-binding parallels lipid solubility
  --> Higher lipid solubility is accompanied by higher protein-binding
• Plasma concentration of the drug
  * Low plasma concentration is more likely to be higher protein bound
• Number of available binding sites (plasma protein)

 

Plasma albumin binding is non-selective
--> Many drugs can compete with each other

For example,

Sulfonamides can displace unconjugated bilirubin from albumin
--> Higher risk of bilirubin encephalopathy in neonates

 

Protein binding and renal failure

In renal failure,
--> Protein-bound fraction of a drug decreases

• Even when plasma protein level is normal
• Possibly due to:
  * Alteration of protein
  * Displacement by a metabolic factor which is normally excreted by kidney

 

Determinants of alpha1-acid glycoprotein level

Alpha1-acid glycoprotein may increase in response to:

• Surgery
• Chronic pain
• Acute MI

 

Alpha1-acid glycoprotein are decreased in neonates
--> Decreased protein binding of diazepam, propanolol, sufentanil, lidocaine