The pharmacokinetics of sertindole were studied in young, healthy volunteers after single and multiple oral dose administered under an escalating manner. In a low-dose study (study 1), subjects received 4-8 mg with a maintenance dose period of 7 days. In a high-dose study (study 2), subjects received 4 mg daily for 2 days, and the dose was increased by 4 mg increments every third day until reaching 20 mg daily. The mean terminal t 1,2 was 73 h after the final 8 mg dose in study 1 and 60 h after the 20 mg dose in study 2. The terminal elimination phase appeared to be monophasic in all the study subjects, suggesting that Michaelis-Menten saturable metabolism was not involved in the elimination of sertindole. Compartmental analyses suggested that the disproportional increase of the Cmax and AUC values from 4 mg to 20 mg during multiple dosing may be explained by saturable presystemic elimination of sertindole, leading to a higher fraction of sertindole available for absorption at higher doses.