Protein-binding

[SH4:p12]

Carriers

• Most acidic drugs binds to albumin
  * High binding capacity
• Basic drugs bind to alpha1-acid glycoprotein
  * Lower binding capacity

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)

Competition for carrier 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

Drugs carried by proteins

[???]

• Albumin binds mostly to acidic drugs
  * Salicylates
  * Sulphonamides
  * Barbiturates
• Alpha1-acid glycoprotein binds mostly to basic drugs
  * Fentanyl
  * Propanolol
  * Diazepam
  * Bupivacaine
  * Ropivacaine
  * Warfarin [???]
  * Quinidine [???]
  * Chlorpromazine [???]
  * Methadone
  * Verapamil [???]
  * Lignocaine [???]

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