This report describes the first study in humans with SDZ HTF 919 (HTF), a novel, selective 5-hydroxytryptamine4 (5-HT4) receptor partial agonist and investigates its tolerability, pharmacokinetics, and pharmacodynamics. Three cohorts of 12 men, of whom 8 were treated with active drug and 4 with placebo, participated in the double-blind, randomized, parallel-group, ascending-dose study. A single dose and subsequently twice-daily multiple doses of 25, 50, and 100 mg were given for 14 days. Adverse events, clinical laboratory variables, electrocardiogram, vital signs, and psychometric effects were recorded. Basic pharmacokinetic characteristics of HTF were derived. Loose stool and total colonic transit time were assessed. Mild to moderate adverse gastrointestinal events, predominantly loose stools, occurred at all dose levels and reflect the pharmacologic properties of HTF. The incidence of headache increased with dose. Dose-normalized (to 25 mg) systemic exposures were 25 +/- 12, 19 +/- 11, and 26 +/- 10 hr.ng/mL in single doses and 26 +/- 12, 23 +/- 12, and 33 +/- 12 hr.ng/mL in multiple doses for the three doses. Steady-state concentrations of HTF were reached after 8 days of daily administration and moderate accumulation was observed. Loose stool occurred on average between 2 and 4 hours after drug administration. The overall HTF-mediated median decrease from baseline (26 and 38 hours) in total colonic transit time was 4.8 hours, versus 1.8 hours with placebo. In conclusion, the novel 5-HT4 receptor agonist HTF was tolerated at oral doses of 25 mg to 100 mg administered twice daily. Pharmacokinetics in both single and multiple doses indicate no deviation from dose proportionality. The applicability of the total colonic transit time as a measurement of surrogate prokinetic effect warrants further investigation in patient populations.