Absorption, distribution, metabolism and excretion of 14C-labelled enantiomers of the calcium channel blocker benidipine after oral administration to rat.

摘要

1. Each of the 14C-labelled optical isomers of benidipine, a new calcium antagonist, was separately administered orally to the male rat at a dose of 0.5 or 1 mg/kg. The absorption, distribution, metabolism and excretion of the 14C-labelled optical isomers were investigated. 2. Plasma concentrations of radioactivity after administration of the (-)-alpha isomer were higher than those after administration of the (+)-alpha isomer. 3. The highest radioactivity was found in liver and high levels of radioactivity were found in the kidney, adrenal gland and lung after administration of the (+)- or (-)-alpha isomers of benidipine. Up to 72 h, the tissue concentration of radioactivity fell from 1.4 to 9.2% of the highest level in each tissue for the (+)-alpha isomer and from 1.8 to 13.0% for the (-)-alpha isomer. 4. The ratios of the area under the time-curve of each tissue concentration to that of the corresponding plasma concentration were almost equal after the separate administrations of both isomers. 5. The dominant urinary and biliary metabolic pathways of the (+)-isomer were the hydrolysis of 1-benzyl 3-piperidylester followed by the oxidation of the dihydropyridine ring and N-dealkylation followed by hydrolysis of the methylester. Those of the (-)-isomer were the hydrolysis of 1-benzyl 3-piperidylester followed by the oxidation of dihydropyridine ring and of the oxidation methyl group, N-dealkylation followed by hydrolysis of the methylester, decarboxylation and glucuronidation of the piperidyl moiety after the oxidation of the dihydropyridine ring. 6. The cumulative excretion of radioactivity in urine and faeces up to 72 h after administration of the (+)-alpha isomer was 8.8 and 90.7% of the dose respectively. The corresponding values of the (-)-alpha isomer were 19.7 and 72.9% of the dose respectively. 7. The excretion of radioactivity in bile up to 48 h after administration of the (+)- and (-)-alpha isomer was 42.1 and 46.7% of the dose respectively.