Nine healthy subjects (7 men; 2 women) received single 20-mg IV injections of 4-aminopyridine (4-AP). Six of the subjects received the same dose in the form of enteric-coated tablets and four the same dose in uncoated tablets; treatments were at least 2 wk apart. Blood, saliva, and urine were assayed for 4-AP using a high-performance liquid chromatography. Kinetic analysis of serum concentrations after intravenous dosing resulted in the best fitting of a triexponential model in five and a biexponential model in four subjects. The apparent volume of distribution (V) was 2.6 +/- 0.9 (mean +/- SD) 1 kg-1, the terminal half-life (t 1/2) 3.6 +/- 0.9 hr, and the total serum clearance 0.61 +/- 0.14 1 hr-1 kg-1. Saliva concentrations were higher than those in serum after 5 min, with a mean correlation coefficient of 0.989 (n = 5). The t 1/2 and V calculated from serum and saliva concentrations were of the same order. The total urinary excretion of unchanged 4-AP was 90.6 +/- 7.8% after intravenous doses and 88.5 +/- 4.8% after oral doses of enteric-coated tablets. The bioavailability of the enteric-coated tablets calculated from the area under the serum concentration curve (95 +/- 29%) did not differ from that calculated from urinary excretion (98 +/- 8%). Protein binding of 4-AP was found to be negligible. Biotransformation is unlikely.