Enantiomer-enantiomer interaction of a calcium channel antagonist, benidipine hydrochloride, during liver metabolism in the rat.

Benidipine hydrochloride is a dihydropyridine calcium antagonist and it is used clinically as a racemate which consists of two optical isomers. The antihypertensive activity of the (+)-alpha isomer is 30-100-fold more potent than that of the (-)-alpha isomer. In rats, after oral administration, plasma concentrations of the (+)-alpha isomer were higher than those after oral administration of the (-)-alpha isomer. In addition, the sum of the plasma concentrations after separate oral administration of each isomer was lower than the plasma concentrations after oral administration of the racemate at a dose equivalent to that of two isomers. The metabolic velocity of the (+)-alpha isomer in male rat liver microsomes was lower than that of the (-)-alpha isomer in the expected liver concentration during absorption, which is consistent with the in vivo results. In rat liver microsomes, each isomer competitively inhibited the metabolism of the other, indicating a metabolic enantiomer-enantiomer interaction of benidipine in the rat.