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The effect of decreased renal function on the disposition and elimination of the nontricyclic antidepressant fluoxetine was examined in 25 adult male subjects after a single 40-mg oral dose. Blood samples for the measurement of fluoxetine and its active metabolite norfluoxetine were drawn 13 times in the first 48 hr after dosing and thrice weekly thereafter for 4 wk. All urine was collected in daily aliquots for 4 wk and was assayed for fluoxetine and norfluoxetine concentrations. The extent of fluoxetine binding to plasma protein was determined by equilibrium dialysis. Kinetic analyses were by noncompartmental methods. The drug and its metabolite were distributed over a large apparent volume and both were eliminated slowly. No correlations between the degree of renal dysfunction and the rate of elimination, volume of distribution, or protein binding were found. Plasma concentrations of fluoxetine and norfluoxetine were not significantly changed by hemodialysis.

The increased availability of chemical intermediates and automated instrumentation has resulted in expanded use of stable isotopes for bioavailability and bioequivalence studies in recent years. Initially, stable isotopes were confined to the labeling of mass internal standard compounds for gas chromatography/mass spectrometry. More recently, their in vivo use has expanded and proved to be a powerful pharmacologic tool. The lack of toxicity of stable isotopes, particularly deuterium and carbon-13, make them ideally suited for human studies. The primary advantage of the isotopic methods is that the drug can be administered concomitantly either by two routes (e.g., parenteral and oral) or in two formulations (e.g., solution and solid dosage). Thus, a single set of blood samples serves to describe the time course of the routes or formulations being compared. The concomitant administration reduces variability inherent in dual administration, the single assay for both forms further reduces variation, and the method minimizes both drug exposure and discomfort to the subject. In addition to single-dose administration, in which two routes or dosage forms are compared, the technique is well suited to "pulse" administration, wherein the kinetics of a single dose, during multiple or chronic dosing regimens, can be compared with single-dose kinetics.

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