Amantadine HCl (3 mg kg-1) was administered orally to 20 young healthy adults. Its apparent volume of distribution (V2/F) was higher in smokers than nonsmokers, 6.05 +/- 0.86 vs 4.87 +/- 0.85 l kg-1; (mean +/- s.d., 10/group, P < 0.011), and no gender-associated effect was observed. Renal clearance did not vary with time-interval, but urinary recovery at 48 h was higher in men than in women (60.2 +/- 7.5% vs 47.0 +/- 15.0%, P < 0.032). Males had higher renal clearances than females when normalised for body mass index (BMI, 0.492 +/- 0.284 vs 0.248 +/- 0.137 l-1 BMI h-1, (10/group, P < 0.032)). On combining data from a previous study, the weight normalised renal clearance was also higher in men than in women, 0.160 +/- 0.075 vs 0.102 +/- 0.053 l kg-1 h-1 (19/group, P < 0.01). Chronic tobacco smoking did not alter the plasma or renal amantadine clearance. We conclude that gender and tobacco smoking are independent variables effecting amantadine disposition.