Stereoselective disposition and metabolism of pinacidil in rat

1. An hplc method has been established for the determination of the enantiomer ratios of pinacidil and pinacidil-pyridine-N-oxide (M-1), using a beta-cyclodextrin-containing mobile phase. 2. Shortly after the administration of racemic pinacidil (2 mg/kg, i.v. or oral) to rat, the enantiomer ((+)/(-)) ratios of pinacidil in plasma were about 1 (i.v.) or > 1 (oral), whereas those of M-1 were < 1; both ratios increased with time. The (+)/(-) ratios of M-1 and pinacidil in 0.24 h urine samples were 0.65 (i.v.), 0.63 (oral), and 2.09 (i.v.), and 1.56 (oral), respectively, in male rat, and 0.76 (i.v.), 0.77 (oral) and 1.79 (i.v.), and 1.48 (oral), respectively, in female rat. 3. No isomerization of (+)- or (-)-pinacidil was observed during incubation with liver slices, and there was no stereoselectivity in the protein binding of the drug. An (-)-enantiomer-rich M-1, however, was produced after incubation of (+/-)-pinacidil with liver slices. The N-oxidation of (-)-pinacidil exhibited a higher stereoselectivity in males than females (the (+)/(-) ratio of M-1 in male, 0.55; female, 0.68). 4. These results indicated that the stereoselective disposition of pinacidil in rat was due, in large part, to the stereoselective N-oxidation of this drug in the liver.