Abstract:The objective of the study was to compare the pharmacokinetics and hemodynamic effects of diltiazem (DTZ) after single dose and multiple doses using an in vivo rat model. Male SD rats (n = 6 -8 per group) weighing between 350 -450 g were used. Each rat received either a single 20mg/kg dose of DTZ or 5mg/kg sc twice daily for 5 doses by subcutaneous (sc) injection. Plasma concentrations of DTZ and its major metabolites were determined by HPLC for up to 8 h. In addition, Systolic Blood Pressure, Diastolic Blood Pressure and Heart Rate were continuously recorded, and analysed using WinNonLin and considered significant when p < 0.05. The results indicate that after the single 20 mg/kg subcutaneous injection, SBP fell from 138 ± 4 to 125 ± 3 mmHg (-9.4%), DBP from 105 ± 3 to 78 ± 4 mmHg (-26%), and HR from 442 ± 12 to 396 ± 7 bpm (-10%). After 5 mg/kg twice daily for 5 doses, the observed SBP was reduced from 127 ± 5 to 111 ± 7 mmHg (-13%), DBP from 108 ± 6 to 88 ± 7 mmgHg (-19%), and HR from 458 ± 11 to 407 ± 22 bpm (-11%). The pharmacokinetics and hemodynamic data were characterized by an Inhibitory Emax model, which showed a similar profile following the single and multiple doses. Multiple regression analyses of the data predicted that the metabolites in particular deacetyl diltiazem (M1) contributed significantly to the blood pressure lowering effects following multiple doses, but the effects of metabolite were minimal after single dose.