Md. Drici et al., Comparison of tegaserod (HTF 919) and its main human metabolite with cisapride and erythromycin on cardiac repolarization in the isolated rabbit heart, J CARDIO PH, 34(1), 1999, pp. 82-88
Citations number
39
Categorie Soggetti
Cardiovascular & Respiratory Systems","Cardiovascular & Hematology Research
Tegaserod (HTF 919) is a new drug being developed for gastrointestinal moti
lity disorders. Because other gastrointestinal prokinetic agents, such as c
isapride and erythromycin, cause slowing of cardiac repolarization and have
been implicated in the development of the potentially fatal ventricular ar
rhythmia, torsades de pointes, a study was initiated to determine whether t
egaserod and its main human metabolite adversely influence cardiac repolari
zation. By using isolated Langendorff-perfused rabbit hearts, we show that
QT intervals remain unchanged at concentrations of tegaserod from 0.5 to 10
mu M. It was not until the tegaserod concentration was increased to 50 mu
M (roughly 500-5,000 times mon concentrated than those typically found in h
uman plasma after administration of recommended clinical dosages), that a s
mall, but significant increase in the QT interval (12 +/- 4%; p < 0.05; n =
4) was observed. No significant changes in QT occurred in the presence of
the tegaserod metabolite at any of the concentrations tested (0.5-50 mu M).
In contrast, cisapride caused QT lengthening at concentrations as low as 0
.1 mu M, with significant QT increases occurring when 5-50 mu M cisapride w
as used (22 +/- 4% to > 70%, respectively; p < 0.01; n = 4). Erythromycin a
lso caused significant lengthening of QT intervals (11 +/- 2%; p < 0.001; n
= 4), although 100 mu M concentrations of this drug were required to achie
ve this effect. These results demonstrate that both cisapride and erythromy
cin can slow cardiac repolarization at therapeutic doses and that tegaserod
's lack of QT prolongation at therapeutic doses suggests that it has the po
tential to be a safer alternative to cisapride as a gastrointestinal prokin
etic agent.