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PLASMA PROTEIN BINDING OF DRUGS

1. Introduction:

Many drugs are extensively bound to plasma proteins. For most such drugs, only the unbound (free) fraction of the total amount in plasma is available for diffusion out of the vascular system to sites of pharmacological activity.

Average values of plasma protein binding for commonly measured drugs in normal subjects:-

Drug	Chemical Class	Percentage Protein-Bound
Amitryptaline	Base	82-96
Carbamazepine	Neutral	70-80
Cimetidine	Base	20
Desipramine	Base	70-90
Digitoxin	Neutral	90-97
Digoxin	Neutral	20
Disopyramide	Base	35-95 (dose dependent)
Gentamicin	Base	< 10
Imipramine	Base	80-95
Lidocaine (Lignocaine)	Base	45-80 (dose dependent)
Lithium	Ion	0
Methotrexate	Acid	50
Noritriptyline	Base	90-95
Phenobarbital	Acid	50-60
Phenytoin	Acid	90-94
Procainamide	Base	15
N-acetylprocainamide	Base	11
Propranolol	Base	90-96
Quinidine	Base	80-90
Salicylate	Acid	50-90
Theophylline	Acid	60
Valproic acid	Acid	80-90

Most of the binding of acidic drugs is to Albumin. The primary drug binding site for acidic drugs on Albumin is apparently the site that binds bilirubin.

Basic drugs bind to Albumin to a small extent and to other serum proteins to a much larger extent.

Eg.

  - acid glycoprotein
- globulin lipoproteins.

2. Protein Binding and Pharmacokinetics:

(a) Distribution:

Vd	=	Vp	+	V .	fu
					____________
					fu
		~3L		Volume outside  plasma into which drug distributes

reduced plasma protein biding (fu) causes an increase in the apparent volume of distribution.

(b) Elimination (Clearance):

Recall:-

Rate of elimination = Cl X C

Cl	=	Q	x	E
		Organ blood flow		Extraction ratio (0 - 1)
	.
	=	Q	x	fu . Cl
				____________
				Q + fu.Cl

Cl = Intrinsic clearance of unbound drug.

 

High E (high Cl):

Cl	Q x	fu . Cl
		________
		fu . Cl
	.
	= Q

Elimination becomes perfusion rate - limited and clearance approaches the organ blood flow. All drugs passing through the organ, whether bound or not, is extracted.

Cl is insensitive to changes in protein binding.

Low E (low Cl):

Cl	Q x	fu . Cl
		________		(Q >> fu.Cl
		Q
	.
	= fu.Cl

Cl is restricted by protein binding, and is independent of organ blood flow.

Therefore, the influence of protein binding changes on clearance depend on the extraction ratio of the drug in question.

 

(i) Hepatic Clearance:

Cl = Q X E

Principles apply as above.

(ii) Renal Clearance:

- Filtration only

Cl  = fu . GFR

- Secretion - generally, Cl is not restricted by protein binding, eg. Penicillins.

- Reabsorption - Cl is dependent on both urine flow rate and fraction of drug unbound.

 

(c) Influence of protein binding on half-life:

t½		0.693 x Vd
	=	__________
		Cl

as fu , in general :

Vd
Cl or

Therefore, depending on the particular drug, t½ may , or show no change with altered plasma protein binding.

 

(d) Protein binding and dosage regimens:

At steady - state:-

(i) Total Plasma Levels:			(ii) Unbound (Free) Level:
C =	F . D		C =	F . D
	_______			_______
	Cl			Cl .
		.
Low extraction drugs:			Low extraction drugs:
fu - Cl - C			No change in Cl - no change in Cu
		.
High extraction drugs:			High extraction drugs:
no change in Cl or C with changes in fu			if fu and C is unchanged then C must

NB With low extraction ratio drugs (eg. Warfarin, Phenytoin), there is no need to alter dosage if the protein binding has changed, eg. drug displacement interactions, as C is unchanged.

With high extraction ratio drugs, there may be a need to adjust dosage.

 

3. Factors Influencing the Extent of Protein Binding:

(a) Drug concentration:

Eg. Salicylate, Disopyramide, Sodium valproate.

(b) Pathophysiological changes - Albumin:

Lead to hypoalbuminaemia:

• Liver disease

• Pregnancy

• Elderly

• Stress

• Malnutrition

• Burns

• Cancer

• Renal failure
  (and retention of endogenous displacing peptroles)

 

(c) Pathophysiological changes - - acid glycoprotein:

acid glycoprotein:

• AMI

• Elderly

• Cancer ­ µ1 acid glycoprotein

• Trauma

• Surgery

• Renal failure

acid glycoprotein:

• Liver disease

• Pregnancy

 

(d) Drug displacement interactions:

Eg. Displacement of Phenytoin by Sodium valproate.

 

4. Monitoring Plasma Levels of Drugs:

Consideration should be given to measuring unbound levels of highly bound drugs (fu < 0.3 - 0.4) in the following circumstances:-

(a) Plasma protein binding of the drug is known to vary considerably between normal patients.

(b) In patients who are likely to have altered binding of the drug (eg. renal disease, pregnancy).

(c) When the extent of biding varies with the total drug concentration (eg. Salicylate).