Steady-state concentrations of a new antidepressant, zimelidine (ZIM), and its active metabolite, norzimelidine (NZIM), were measured in plasma and cerebrospinal fluid (CSF) in eight depressed patients. Free drug, as calculated from the ratio of CSF to plasma concentration, of ZIM was 8.4 +/- 1.8% and of NZIM was 18.3 +/- 2.8%. Equilibrium dialysis (ED) of plasma from the same patients on placebo yielded free fractions of 8.6 +/- 2.2% and 28.1 +/- 3.4% for the two compounds. alpha 1-Acid glycoprotein (alpha a-AG) was also measured in the same samples. Variation in free drug using either method was not great, but did modestly correlate with alpha 1-AG concentration in six of the eight patients in whom simultaneous placebo measures were available. Our results indicate that measurements in plasma or of free drug dependent on ED lead to erroneous conclusions regarding the proportion of free NZIM to ZIM. Considering the different potencies of the parent compound and active metabolite, this is an unusual problem.