Objective: To evaluate the effect of grapefruit juice on the pharmacokinetics of artemether in plasma and saliva after a single oral dose and to detect concentration-dependent electrocardiographic changes (bradycardia and QT(c) prolongation). Methods: Six healthy male subjects were given a standard breakfast followed by two tablets of 50-mg artemether administered with water; l week later, the tablets were administered with 350 ml double-strength fresh frozen grapefruit juice. For 8 h, 17 blood- and saliva samples were collected, and 17 electrocardiograms were recorded. Drug and metabolite concentrations were measured by means of high-performance liquid chromatography with electrochemical detection. The pharmacokinetic parameters were determined using a one-compartment model. Results: Grapefruit juice significantly (P = 0.001) increased the mean peak concentration (C(max)) of artemether more then twofold from 42 (SD 17) ng/ml to 107 (28) ng/ml. The time to reach C(max) (t(max)) with grapefruit juice was 2.1 (0.6) h compared with 3.6 (17) h with water (P = 0.02). The area under the concentration-time curve (AUC) almost doubled with grapefruit juice from 177 ng · h/ml to 336 ng · h/ml (P = 0.003). The elimination half-life remained unchanged (1.0 h vs 1.3 h). No major changes in the kinetics of the metabolite dihydroartemisinin were detected. Low artemether levels and zero dihydroartemisinin levels were found in saliva. No influences of artemether were observed on 17 electrocardiograms during the 8 h after drug intake - in particular there were no signs of bradycardia or QT(c) prolongation. Conclusion: Grapefruit juice significantly increases the oral bioavailability of artemether without an effect on the elimination half-life. It suggests a role for intestinal CYP3A4 in the presystemic metabolism of artemether.