Pharmacokinetics of ibutilide and its enantiomers in dogs

Ibutilide fumarate, a new drug for the treatment of cardiac arrhythmias, contains a stereogenic center bearing a secondary alcohol group. Several single dose and multiple dose studies of racemic ibutilide or its enantiomers were performed by the oral and intravenous routes in dogs. 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 enantiomers exhibited high clearance rates, large volumes of distribution, and low oral bioavailability. As the dose increased, pharmacokinetic differences between the enantiomers were observed. The greatest differences (3-fold) were seen after oral administration at 4 mg/kg, indicating that first-pass metabolism of ibutilide was highly enantioselective at high doses. The clearances of the enantiomers differed by up to 34% at 5 mg/kg followed intravenous administration of the racemate. At high 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 bioavailability of the racemate increased from 2% at 0.3 mg/kg to as much as 84% at 5 mg/kg.