Free Drug Monitoring


Drugs are bound to various serum proteins in different degrees varying from 0% protein binding to 99% protein binding, but only unbound or free drug is pharmacologically active. Although free drug concentration can be estimated from total concentration knowing the extent of protein binding of a particular drug, for strongly bound drugs (more than 80% bound to serum protein), prediction of free level is not always possible. Conditions such as uremia, liver disease and hypoalbuminemia can lead to significant increases in free drug resulting in drug toxicity although the total drug concentration may be within the established therapeutic range. Drug–drug interactions are another major cause for disproportionate increases in free drug concentrations. Currently, free drug concentrations of anticonvulsants such as phenytoin, carbamazepine and valproic acid are widely measured in clinical laboratories. Newer drugs such as mycophenolic acid mofetil and certain protease inhibitors are also considered as good candidates for monitoring free drug concentration.

Key Concepts:

  • There are rationales for monitoring free drug concentration only for drugs that are strongly bound to serum proteins (80% or more).

  • Why free concentrations of phenytoin, valproic acid and carbamazepine are frequently monitored in certain patient population?

  • There is a need for monitoring free drug levels in uremia due to impaired protein binding of drugs as well as displacement of certain drugs from protein binding by ceratin uremic toxins.

  • There is a need for monitoring free drug concentrations in hepatic diseases due to impaired protein binding of certain drugs.

  • There is a need for monitoring free drug concentration in patients with hypoalbuminemia and critically ill patients due to elevated concentrations of free levels of drugs secondary to impaired protein binding.

  • There is a need for monitoring free drug concentrations in pregnancy due to change in protein binding and various other factors that affect clearance of certain drugs.

  • There is a need for monitoring free drug concentrations in AIDS patients due to impaired protein binding and probable drug–drug interactions.

  • Future candidates for monitoring free drugs include mycophenolic acid and protease inhibitors because these drugs are strongly bound to albumin and also have narrow therapeutic index.

  • Special case of monitoring free drug concentrations is digoxin, which is only 25% bound to serum proteins, but monitoring free digoxin in patients being treated with Digibind or taking certain herbal supplements is helpful to get clinically meaningful results.

Keywords: free drugs; anticonvulsants; immunosuppressant; protein binding; clinical utility

Figure 1.

Chemical structures of frequently monitored free drugs: phenytoin, carbamazepine and valproic acid.

Figure 2.

Chemical structures of bufalin, oleandrin and digoxin.



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Further Reading

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Dasgupta, Amitava(Feb 2011) Free Drug Monitoring. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0023211]