Metabolic fate of diltiazem. Distribution, excretion and protein binding in rat and dog

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 microgram/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 micrograms/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 tissues and organs of rats.(ABSTRACT TRUNCATED AT 250 WORDS)