Amitava Dasgupta PhD


1. Introduction

2. Drugs Which are Candidate for Free Drug Monitoring

3. Monitoring Concentrations of Free Anticonvulsants

4. When Should Free Anticonvulsant Be Monitored?

5. Elevated Free Anticonvulsant Concentrations in Uremia

6. Drug-Drug Interactions and Elevated Free Anticonvulsant Concentrations

7. Saliva and Tears: Alternative to Serum for Therapeutic Drug Monitoring

8. Assay Techniques for Free Anticonvulsants

9. Conclusions


Measurement of serum drug concentration may be misleading for a strongly protein-bound drug because a drug bound to protein is inactive and only unbound or free drug is pharmacologically active. Although free drug concentration can be estimated from total concentration in most cases, under certain pathophysiological conditions such as uremia, liver disease, and hypoalbuminemia free drug concentration may be significantly elevated even if the concentration of the total drug is within therapeutic range. Drug-drug interactions may also lead to a disproportionate increase in free drug concentrations. Elderly patients usually show increased free drug concentrations because of hypoalbuminemia. Elevated free phenytoin concentrations have also been reported in patients with AIDS and pregnancy. 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 candidates for monitoring free drug concentration.

Key Words: Free drugs; anticonvulsants; immunosuppressant; protein binding; clinical utility.

From: Handbook of Drug Monitoring Methods Edited by: A. Dasgupta © Humana Press Inc., Totowa, NJ

1. introduction

Therapeutic drug monitoring is defined as the management of a patient's drug regime based on serum, plasma, or whole blood concentration of a drug. Therapeutic drug monitoring is valuable when the drug in question has a narrow therapeutic index and toxicity may be encountered at a concentration slightly above the upper end of the therapeutic range. The protein binding of a drug can be low, moderate, or high (> 80%). Some drugs such as ethosuximide and lithium are not even bound to serum proteins (0% binding). Albumin, aracid glycoprotein and lipoproteins are major drug-binding proteins in serum. Drugs exist in peripheral circulation as free (unbound) and bound to protein forms following the principle of reversible equilibrium and law of mass action. Only free drug can bind with the receptor for pharmacological action, and concentrations of active drug molecule at the receptor site is generally considered as related to unbound (free) drug concentration in plasma (1).

In general, there is equilibrium between free drug and protein-bound drug.

[D] is unbound drug concentration, [P] is binding protein concentration, [DP] represents drug/protein complex, and K is the association constant (liters/mole). The greater the affinity of the protein for the drug, the higher is the K value. The free fraction of a drug represents the relationship between bound and free drug concentration and is often referred as "Fu".

p Free drug concentration u

Total drug concentration (bound + free)

Free fraction (Fu) does not vary with total drug concentration because protein-binding sites usually exceed the number of drug molecules present. Therefore, unbound concentration of a drug can be easily calculated by multiplying total drug concentration with Fu, and there maybe no need to measure free drug directly.

Free drug concentration = Fu x Total drug concentration

For example, phenytoin is 10% free (Fu = 0.1). Therefore, if total phenytoin concentration is 10 ^g/mL, the free concentration should be 1 ^g/mL. However, for certain drugs, the number of protein-binding sites may approach or be less than the number of drug molecules. Valproic acid exhibits saturable protein binding at the upper end of the therapeutic range and as a result the Fu of valproic acid is subject to more variation than other highly protein-bound antiepileptic drugs (2,3). For example, albumin concentration of 4.0gm/dL is equivalent to an albumin concentration of 597 ^mol/L because the molecular weight of albumin is 67,000 D. The therapeutic range of valproic acid is 50-100 ^g/mL or 347-693 ^mol/L. Therefore, the upper end of therapeutic molar concentration of valproic acid exceeds molar concentration of albumin and not enough binding sites are available to bind valproic acid. Other factors also may influence the Fu such as displacement of a strongly protein-bound drug by another strongly protein-bound drug or endogenous factors.

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