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The extent of drug binding to plasma protein does not influence the concentration of unbound drug in plasma at steady state but does influence the interpretation of total drug concentrations. An increase in free fraction (reduction in the extent of binding) decreases the therapeutic and toxic ranges for total drug concentrations. Conversely, a reduction in free fraction (increase in the extent of binding) increases these ranges. Laboratories generally measure total rather than unbound drug concentrations, and clinicians must use caution in interpreting these total drug concentrations in clinical situations where the extent of binding of extensively bound drugs may be altered. Free drug serum or plasma concentrations are inherently more reliable indices of the intensity of drug action than are total concentrations. Methodology for routine measurement of free concentration is becoming available and should ultimately be utilized for therapeutic monitoring of drugs that are highly bound to protein.

The importance of individualizing the dosage of potent drugs in order to maximize their therapeutic effectiveness and safety is generally accepted. Whenever possible the dosage of a drug should be "titrated" directly in each patient against the intensity of its therapeutic or toxic actions. Unfortunately, for many drugs convenient clinical yardsticks of the intensity of their pharmacologic effects are lacking. Determination of the serum concentration of such compounds can help to guide adjustment of dosage during their therapeutic use. By measuring the serum level of drugs one bypasses the largest source of individual differences in dose-effect relationships-the pharmacokinetic variation between subjects. However, the relationship between the serum concentration of a drug and the intensity of its pharmacodynamic action is influenced by many other factors, which must always be considered in interpretation of serum levels. Therapeutic decisions should never be based soley on the serum concentration of a compound, nor can such measurements ever substitute for careful medical observation and judgement.

The absorption of oral digoxin preparations has been a topic of much concern during the last 5 years. The completeness of digoxin absorption is proportional to the area under the serum concentration time curve and to the urinary excretion of digoxin after single doses. During chronic therapy the completeness of absorption is proportional to these values and also to the steady state serum concentration. Determination of absolute bioavailability of a given digoxin preparation requires a comparative study using intravenous digoxin as a standard. Oral digoxin solutions are incompletely absorbed, but have biological availability greater than or equal to that of tablets. The absorption of digoxin tablets depends upon their dissolution rate which in turn is related to drug particle size. Digoxin tablets with small drug particles have rapid rates of dissolution and can be absorbed as completely as oral solutions. The bioavailability of digoxin from tablets can be influenced by changes in gastro-intestinal motility, malabsorption syndromes, and by co-administration of food or other drugs. New regulations now insure that all marketed digoxin tablet preparations have satisfactory bioavailability. Problems with biological availability at present are unlikely to account for unexpected clinical results during digoxin therapy.

Determination of serum concentrations of certain drugs is becoming increasingly important for optimal patient care. These drugs include many antibiotics, several antiarrhythmics, cardiac glycosides, lithium, phenytoin, some other anticonvulsants, salicylates, and theophylline. Serum level determinations can also be useful for establishing the best individual dosage of benzodiazepines, phenothiazines, and tricyclic antidepressants. On the other hand, information about serum levels is not necessary or useful for many widely used drugs. In general, measurement of serum concentrations is valuable only for drugs whose dosage should be individualized and whose therapeutic and toxic actions are not adequately quantifiable by clinical endpoints. The serum concentration of the drug and of important active metabolites must be accurately measurable, the relation between their concentrations in the serum and the intensity of therapeutic and toxic effects during clinical use must have been clearly defined, and serum levels must always be knowledgeably interpreted in conjunction with careful clinical observation and judgment. Measurements of serum drug concentrations are most often useful during prophylactic drug therapy, in patients with major pharmacokinetic disturbances, and when patients show unusual and unexplained sensitivity or resistance to therapy with a drug.