METABOLIC-FATE OF DILTIAZEM - DISTRIBUTION, EXCRETION AND PROTEIN-BINDING IN RAT AND DOG

  • 1 November 1987
    • journal article
    • research article
    • Vol. 37-2  (11) , 1244-1252
Abstract
Pharmacokinetics of (+)-(2S,3S)-2,3-dihydro-3-acetoxy-2-(4-methoxyphenyl)-5-[2-(dimethylamino)ethyl]-1,5-benzothiazepin-4(5H)-one hydrochloride (diltiazem-HCl, Cardizem, Herbesser) in rats and dogs were investigated using 14C-diltiazem-HCl. The plasma concentration of unchanged drug in rats was 1.78 .mu.g/ml 1 min after intravenous administration at a dose of 3 mg/kg, and rapidly decreased thereafter with a half-life of 20 min (.alpha.-phase) and 56 min (.beta.-phase). In contrast, the plasma concentration of radioactivity in rats increased during 0-2 h in spite of intravenous administration, and thereafter the level of radioactivity in plasma decreased very slow. In dogs, the plasma concentration of unchanged drug was 0.138 .mu.g/ml 1 min after intravenous administration at a dose of 0.2 mg/kg, and then decreased with a half-life of 2.5 min (.alpha.-phase) and 1.68 h (.beta.-phase). Dog plasma level of radioactivity decreased once after intravenous administration, but increased from 30 min to 1 h. Unchanged drug plasma levels at 1 h after intravenous administration were 6.6 and 35.1% of the plasma radioactivities in rats and dogs, respectively. When 14C-diltiazem-HCl was orally administered, unchanged drug plasma levels in rats and dogs were 1.8 and 12.8% of the plasma radioactivities at 15 min, respectively. Therefore, the first-pass effect was extensive, especially in rats. Rat whole body autoradiograms showed that radioactivity distributed well to tissues and organs in either route of administration. Similar results were obtained by the method of counting the radioactivity in the tissue and organs of rats. High radioactivity was found in the liver, lung, kidney, cardiac muscle, adrenal gland, pituitary gland, pineal body, intestinal wall and Harder''s gland. The radioactivity in blood was low. Levels of radioactivity in milk were parallel to those in plasma. In rats, the cumulative excretion rates of radioactivity into urine and feces were, irrespective of dosage route, about 35 and 65% up to 72 h, respectively. Both cumulative excretion rates of radioactivity into dog urine after intravenous and oral administration were about 32% up to 48 h, and fecal excretion rates in dog were about 68 and 63% up to 48 h after intravenous and oral administration, respectively. Biliary excretion rates in rats were also about 65% in either route of administration. These results indicate that this drug was well absorbed from gastrointestinal tracts, and that a large amount of radioactivity was excreted into feces via biliary excretion. Enterohepatic circulation of this drug was noticed. The percentage of diltiazem bound to rat plasma proteins in vitro was 66-85% according to drug concentration, while that to human plasma proteins was 55-65%. In in vivo experiments, the percentage of diltiazem bound to rat plasma proteins was about 88-99% after intravenous administration.