Nakamura S, Ito Y, Fukushima T, Sugawara Y, Ohashi M
Biological Research Laboratory, Tanabe Seiyaku Co., Ltd., Saitama, Japan.
J Pharmacobiodyn. 1990 Oct;13(10):612-21. doi: 10.1248/bpb1978.13.612.
The main metabolites of diltiazem in rats are acidic metabolites having a carboxyl group which may be formed by oxidative deamination of the dimethylaminoethyl group of diltiazem. In order to identify the enzymes responsible for the deamination and formation of acidic and neutral metabolites [14C]diltiazem was incubated with microsomal and mitochondrial preparations from the liver of SD male rats. Both acidic and neutral metabolites were formed only in the presence of an nicotinamide adenine dinucleotide phosphate generating system. Their formation was remarkable, especially in the microsomes, and inhibited by SKF 252-A, but not by pargyline and iproniazid. The production of neutral metabolites surpassed that of acidic ones. Structural analysis by gas chromatography-mass spectrometry showed that the neutral metabolites are aldehydes which have not been detected in vivo. The results suggest that the dimethylaminoethyl group of diltiazem is oxidized to an aldehyde group by microsomal cytochrome P-450 in the liver. Subsequently, the aldehyde group would be dehydrogenated to the carboxyl group.
地尔硫䓬在大鼠体内的主要代谢产物是具有羧基的酸性代谢产物，其可能由地尔硫䓬的二甲氨基乙基经氧化脱氨形成。为了鉴定负责脱氨以及酸性和中性代谢产物形成的酶，将[14C]地尔硫䓬与SD雄性大鼠肝脏的微粒体和线粒体制剂一起孵育。酸性和中性代谢产物仅在存在烟酰胺腺嘌呤二核苷酸磷酸生成系统的情况下形成。它们的形成很显著，尤其是在微粒体中，并且受到SKF 252 - A的抑制，但不受帕吉林和异烟肼的抑制。中性代谢产物的生成超过了酸性代谢产物。通过气相色谱 - 质谱联用进行的结构分析表明，中性代谢产物是醛类，在体内尚未检测到。结果表明，地尔硫䓬的二甲氨基乙基在肝脏中被微粒体细胞色素P - 450氧化为醛基。随后，醛基会脱氢形成羧基。
