The Whole Body Autoradiographic Studies on the Distribution of <SUP>14</SUP>C-Labeled New 1, 5-Benzothiazepine Derivative (<SUP>14</SUP>C-CRD-401) in Mice

Abstract

The distribution of a "C-labeled coronary vasodilator, 3-acetoxy-2, 3-dihydro-5-[2-(dimethylamino) ethyl]-2-(p-methoxyphenyl)-1,5-benzothiazepin-4 (5H)-one hydrochloride-(14C-CRD-401), in mice was studied by means of whole body autoradiographic technique. Immediately after intravenous injection, 14C-CRD-401 disappeared from the blood and accumulated in the heart muscle, lung, adrenal cortex, kidney, skeletal muscle and brain. The high radioactivity appeared rapidly in the stomach mucosa and bile, and consequently in the lumen of the stomach and intestine. Most organs which exhibited the highest radioactivity immediately after the injection showed gradually diminishing radioactivity during the first 24 hours. When administered orally to mice, 14C-CRD-401 was rapidly and easily absorbed from the intestinal tract, and the radioactivity in various organs reached their maximal levels within 30 minutes. The experiments with pregnant mice administered 14C-CRD-401 intravenously and orally demonstrated that there was a slow and slight penetration of radioactive materials to the fetuses through the placenta. Chromatographic investigation on the tissue-extracts of mice treated with 14C-CRD-401 demonstrated the compound was rapidly metabolized in mice after intravenous administration as well as after oral one.

Effects of Verapamil and Diltiazem on Dopamine Release in the Central Nervous System of Spontaneously Hypertensive Rats

“…A study with autoradiographic techniques showed that a high concentration of the Ca2+-antagonist was observed in the brain when the drug was intravenously and orally administered (Sakuma et al 1971). It is possible that the modulation of central dopamine release by the Ca2+-antagonists is related to their hypotensive effects in hypertension.…”

“…It is well recognized that compounds classed as Ca2+antagonists have an effective antihypertensive action in clinical use (Nayler 1980). An autoradiographic study demonstrated that a high concentration of diltiazem was observed in the brain and spinal cord when it was intravenously and orally administered to mice (Sakuma et al 1971). Doran el al.…”

Diltiazem

“…In the rodent, orally administered diltiazem is readily absorbed from the gastrointestinal tract. In a study on mice in which 14C-diltiazem (20 mg/kg) was administered, radioactivity reached maximal levels within 5 min in the liver and within 30 min in all other organs studied (114). Pyloric ligation resulted in a marked decrease in radioactivity within the organs, indicating that absorption occurs primarily in the intestine (114).…”

“…In a study on mice in which 14C-diltiazem (20 mg/kg) was administered, radioactivity reached maximal levels within 5 min in the liver and within 30 min in all other organs studied (114). Pyloric ligation resulted in a marked decrease in radioactivity within the organs, indicating that absorption occurs primarily in the intestine (114). In a similar study on rats, I4C-diltiazem (5 mg/kg) administered orally had a gastrointestinal absorption half-life of 26 min (69).…”

Suppression of atherosclerosis in cholesterol-fed rabbits by diltiazem injection.

“…The pharmacological effect of this amount on hemodynamics would correspond to 400 mg/kg of orally administered diltiazem. 24 The oral dose of diltiazem in the studies by Naito et al and Ginsburg et al was about 100 mg/kg, about three times the clinical dose used for humans. Further studies on this point are needed.…”