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 (+)-α isomer is 30–100-fold more potent than that of the (−)-α isomer. In rats, after oral administration, plasma concentrations of the (+)-α isomer were higher than those after oral administration of the (−)-α 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 (+)-α isomer in male rat liver microsomes was lower than that of the (−)-α isomer in the expected liver concentration during absorption, which is consistent with thein 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.