Clinical utility of free drug monitoring

Most drugs are bound to serum proteins to a various degree. Only unbound or free drug is pharmacologically active. Usually total drug is measured for therapeutic monitoring because there is equilibrium between bound and free drugs, and concentration of free drug can be predicted from total drug concentration. However, under certain conditions this equilibrium disturbed and the measured free drug concentration can be significantly higher than expected from total drug concentrations, especially for strongly proteinbound drugs. In such case a patient may experience drug toxicity even if the total drug concentration within the therapeutic range. Conditions like uremia, liver disease and hypoalbuminemia can lead to significant increases in free drug concentration. Therefore, monitoring free phenytoin and free valproic acid is recommended in these patients. Drugdrug interactions can also lead to a disproportionate increase in free drug concentration. One strongly proteinbound drug can significantly displace another strongly proteinbound drug if both drugs share the same binding site. Several overthecounter pain medications such as salicylate, naproxen, and ibuprofen can cause significant displacement of both phenytoin and valproic acid from albumin binding site. Interestingly, such interactions are absent in uremic patients. Elderly patients may have increased free phenytoin or valproic acid due to hypoalbuminemia. Elevated free phenytoin concentrations have also been reported in patients with AIDS. Although digoxin is 25% bound to protein, monitoring free digoxin is useful in patients with elevated endogenous digoxinlike immunoreactive substances or in patients overdosed with digoxin and being treated with digibind. Monitoring free digoxin can also eliminate interference of Chinese medicines Chan Su and Danshen in serum digoxin measurement by certain immunoassays. However, free drug monitoring is not routine procedure in clinical laboratories due to technical difficulties and lack of established reference ranges for free drugs.