PHARMACOKINETICS OF IBUTILIDE AND ITS ENANTIOMERS IN DOGS

Ibutilide fumarate, a new drug for the treatment of cardiac arrhythmia s, contains a stereogenic center bearing a secondary alcohol group. Se veral single dose and multiple dose studies of racemic ibutilide or it s enantiomers were performed by the oral and intravenous routes in dog s. A chiral assay was used to examine racemization and the individual enantiomer pharmacokinetics. Following low oral or intravenous doses ( approximately 0.3 mg/kg), the pharmacokinetics of the enantiomers were nearly identical, with no substantial chiral conversion. Both enantio mers exhibited high clearance rates, large volumes of distribution, an d low oral bioavailability. As the dose increased, pharmacokinetic dif ferences between the enantiomers were observed. The greatest differenc es (3-fold) were seen after oral administration at 4 mg/kg, indicating that first-pass metabolism of ibutilide was highly enantioselective a t high doses. The clearances of the enantiomers differed by up to 34% at 5 mg/kg followed intravenous administration of the racemate. At hig h doses, other non-linear pharmacokinetic behavior was also apparent. The intravenous clearance of ibutilide declined from 5.3 L/h/kg at 0.3 mg/kg to 3.7 L/h/kg at a dose of 5 mg/kg. The absolute oral bioavaila bility of the racemate increased from 2% at 0.3 mg/kg to as much as 84 % at 5 mg/kg. (C) 1996 Wiley-Liss, Inc.