Interpretation of drug levels: relevance of plasma protein binding

Many centrally acting drugs bind extensively to plasma proteins, particularly albumin. It is generally the free concentration rather than the total concentration which determines the intensity of pharmacological action and the distribution and rate of elimination of a drug. Measurement of the total plasma concentration may therefore give a false idea of the amount of active drug available. Furthermore, variation in the degree of binding from one subject to another, and displacement of drug molecules by a second drug, may complicate the interpretation of serum levels when both bound and free drug are measured together. The strict use of therapeutic ranges of serum levels may therefore be harmful when a larger than normal proportion of the drug is free. In theory, monitoring the free concentration would have advantages, but on a routine basis this is not practical at present for technical reasons. Cerebrospinal fluid is an ultrafiltrate of plasma but lumbar puncture for routine monitoring purposes cannot be justified. Monitoring salivary concentrations is a practical alternative but for some drugs variation in the degree of ionization of the compound may make salivary levels unreliable.