Pharmacokinetics and Haemodynamic Effect of Diltiazem in Rats: Effect of Route of Administration

Diltiazem is a calcium antagonist widely used for the treatment of angina and hypertension. Previous studies in patients have shown that the haemodynamic effects of diltiazem are greater after parenteral rather than oral administration. The rat has been used as an animal model to determine the effect of the route of administration on the pharmacokinetic and haemodynamic effects of diltiazem. The results showed that plasma concentrations of diltiazem were more than 10 times higher after the intra‐arterial dose. The plasma concentrations of the major metabolites were also higher after intra‐arterial administration, although only for deacetyl diltiazem (M1) did the difference reach statistical significance (P < 0.05). The haemodynamic effects (on blood pressure and heart rate) of diltiazem were considerably greater after intra‐arterial administration; this was attributed mainly to the much higher plasma concentrations of diltiazem. The hypotensive and chronotropic effects of diltiazem were similar; Emax and EC50 for diastolic blood pressure were 72 ± 19% and 4.4 ± 5.9 μg mL−1; for heart rate they were 77 ± 32% and 10.0 ± 11.7 μg mL−1, respectively. The haemodynamic effects of diltiazem are much greater after intra‐arterial administration, mainly because of the much higher plasma concentrations of the drug. The contribution by the metabolites would be minimal after this route of administration.