Monitoring

If the protein binding of a drug is less than 80%, it is not considered a candidate for free drug monitoring because variation in protein binding may not have clinically significant effect in altered free drug concentrations. For example, if a drug is 90% protein bound and the protein binding is decreased by 10%, the Fu is increased by 90%. If the drug is 80% protein bound, reduction of protein to 72% will result in an Fu increase from 2.0 |g/mL (assuming again total drug concentration is 10 |g/mL) to 2.8 |g/mL, a 40% increase. If the drug is only 50% bound to serum protein, a 10% reduction in protein binding will only alter free drug concentration by 10% (Fig. 1). An exception is free digoxin monitoring (digoxin is only 25% protein bound), which is very useful in patients overdosed with digoxin and being treated with digibind, the Fab fragment of antidigoxin antibody. Protein binding of some commonly monitored therapeutic drugs is given in Table 1. In today's practice, free drug monitoring is most common with anticonvulsants.

The first comprehensive report demonstrating the clinical utility of free drug monitoring dated back to 1973 (4). In a population of 30 epileptic patients, the authors found a better correlation with toxicity (in coordination, ataxia and nystagmus) and free drug concentrations. Blum et al. described a uremic patient who was well controlled on a total phenytoin concentration of 3 |g/mL, which was far below the recommended

Fig. 1. Percentage change in free drug concentration because of a 10% reduction in protein binding of a drug. Calculations are based on a total drug concentration of 10 |ig/mL. Range of protein binding of drug is from 20 to 90%.

Table 1

Protein Binding of Commonly Monitored Therapeutic Drugs

Table 1

Protein Binding of Commonly Monitored Therapeutic Drugs

Drug

Protein Binding (%)

Protein Type

Free Drug Monitoring

Amikacin

<5

No

Kanamycin

<5

No

Ethosuximide

0

No

Procainamide

10-15

Albumin

No

Theophylline

40

Albumin

No

Phenobarb

40

Albumin

No

Phenytoin

90

Albumin

Yes

Carbamazepine

80

Albumin

Yes

Valproic acid

90-95

Albumin

Yes

Primidone

15

Albumin

No

Digoxin

25

Albumin

Yes

Quinidine

80

a-1-acid glycoprotein

Yes

Lidocaine

60-80

a-1-acid glycoprotein

Yes

Cyclosporine

98

Lipoproteins

Yes

Tacrolimus

97

Lipoprotein

Yes

Mycophenolic acid

92

Albumin

Yes

therapeutic range of 10-20 ^g/mL (5). The most likely cause of this observation was significantly elevated Fu of phenytoin because of uremia.

Albumin and a1-acid glycoprotein are the major drug-binding proteins in serum. At least two drug-binding sites with different domains have been identified in albumin, and a drug may bind to one or both sites. Basic drugs usually bind to either a single protein such as albumin or an a1-acid glycoprotein. Alternatively, basic drugs may also bind to several proteins including lipoproteins. The concentration of a1-acid glyco-protein may increase in several disease states thus may cause reduced Fu of a free basic drugs. Such conditions are given in Table 2. Acidic drugs predominately bind to albumin, although interactions with a1-acid glycoprotein have also been reported. The concentration of album decreases significantly under several pathophysiological conditions leading to an increase in Fu of acidic drugs. Such conditions are summarized in Table 3.

Drug protein binding may also change with temperature and pH. For basic drugs, the percentage of unbound drug decreases with increasing pH, but for acidic drugs, the unbound fraction may increase, decrease, or remain independent of pH change (6).

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