Pharmacokinetics of diltiazem and deacetyldiltiazem in rats

Abstract

Diltiazem (DTZ) was given intravenously (i.v.), orally (p.o.) and hepatoportally (p.v.) in solution form to rats in order to assess the pharmacokinetic behavior of DTZ and its major metabolite, deacetyldiltiazem (DAD). The plasma half-life at postdistributive phase ( t 1 2 ,β), total body (plasma) clearance (CL t) and volume of distribution at steady-state (Vd ss) of DTZ were 38.3 min, 90.3 ml/min per kg and 3595 ml/kg, respectively, for a 3 mg/kg i.v. dose. DAD was also given to rats through the i.v. route and its plasma pharmacokinetics was compared with that of DTZ. The t 1 2 ,β, CL t and Vd ss of DAD were 43.3 min, 82.4 ml/min per kg and 4042 ml/kg, respectively, for a 3 mg/kg i.v. dose. There was no significant difference in the pharmacokinetic parameters between DTZ and DAD. 20% of the i.v. dose was found to be metabolized to DAD in the body. Most of an oral dose of DTZ (30 mg/kg was extracted during its passage through the GI tract and only 15% of the dose was transported into the portal venous blood as an intact form. DTZ administered by the p.v. route (10 ml/kg) suffered hepatic extraction and 37% of the dose could reach the systemic circulation. As a consequence, bioavailability of only 6% could be obtained for the oral DTZ.