Cardiovascular effects of the R- and S-enantiomers of ibutilide in conscious beagle dogs.
To support its class III antiarrhythmic candidacy, we examined the acute cardiovascular effects of ibutilide and its R- and S-enantiomers in conscious beagle dogs. Eight dogs were given stepped i.v. doses (0.01, 0.1, and 1.0 mg/kg) of these agents while monitoring changes in mean arterial pressure (MAP), heart rate (HR), and lead II ECG QTc length (index of class III activity). None of the treatments affected MAP and only R-ibutilide slightly increased HR. The R-isomer was also slightly more potent in prolonging QTc at the lowest dose, but its mean peak QTc change (+44 msec) overlapped those achieved with racemic (+37 msec) and S-ibutilide (+41 msec). Plasma drug analyses showed that total drug levels (sum of enantiomers) were similar with each agent, averaging 1, 12, and 170 ng/ml at 30 min after the low, middle, and high doses, respectively. Nearly equal enantiomer proportions were seen after racemic ibutilide, and no chiral inversion was seen after enantiomer administration. All treatments were well tolerated without enhanced ventricular ectopy. These data demonstrate that in conscious dogs, racemic, R-, and S-ibutilide similarly prolong QTc independent of appreciable cardiovascular changes, differential pharmacokinetics, or dysrhythmias, thereby helping to establish racemic ibutilide as the optimal developmental candidate.
Humphrey
S J
SJ
Pharmacology Units, Pharmacia Corporation, Kalamazoo, Michigan, USA. stephen.j.humphrey@pharmacia.com
Smith
M P
MP
Hsu
C Y
CY
Walters
R R
RR
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D004285:Dogs; D004562:Electrocardiography / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D008133:Long QT Syndrome / Q000188:drug therapy / Q000503:physiopathology; D013237:Stereoisomerism; D013449:Sulfonamides / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D018879:Ventricular Premature Complexes / Q000188:drug therapy
D000889:Anti-Arrhythmia Agents; D013449:Sulfonamides; C067192:ibutilide