Free (non-protein bound) drug monitoring is very complex but new advances in separation of protein bound from free drug by ultrafiltration can facilitate free concentration therapeutic drug monitoring. Free drug can be separated from protein-bound drug by means of ultrafiltration in which the free drug passes through the membrane filter while the protein bound drug is retained. The ultrafiltrate is then subjected to chromatographic analysis (HPLC). Limitations include a sufficient sample for these highly protein bound drugs and detector sensitivity at the low free drug concentrations. Free drug fractions that have been successfully analyzed by HPLC include disopyramide, phenytoin, carbamazepine, and propranolol. HPLC offers important advantages over immunoassays, since chromatographic methods can also measure the amount of metabolite present. The detection of metabolites can be important, e.g. N-desisopropyl disopyramide which displaces disopyramide from its binding sites on alpha-one acid glycoprotein. The main controversies concerning free drug concentration monitoring have revolved around the time expenditure as well as clinical significance of changes in free fraction. Obtaining free and total drug concentrations of monitored drugs permits an assessment of the free fraction of drug and provides pharmacokinetic parameters for more accurate dose prediction and dose adjustment, in which HPLC can offer an attractive method of analysis.
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