The objective of the study was to determine the effect of repeated administration on the pharmacokinetics and metabolism of diltiazem (DTZ) using an in vivo rat model. Male SD rats (n = 6-10 per group) weighing 350-450 g were used. Each rat received either a single 20 mg/kg dose of DTZ by subcutaneous (s.c.) injection or 5 mg/kg s.c. twice daily for five doses. Plasma concentrations of DTZ and its major metabolites were determined by HPLC for up to 8 h. Compared with the single dose, repeated administration resulted in higher dose normalized plasma concentrations of DTZ (AUC 26.4+/-14.2 vs 13.9+/-11.5 microg-h/ml), longer apparent half-life (t(1/2) = 12.5+/-14.6 vs 3.7+/-1.4 h) and lower systemic clearance (CL = 1.1+/-1.0 vs 2.9+/-2.7 l/h/kg). Higher dose normalized plasma concentrations, longer t(max), but shorter apparent t(1/2) of the major metabolites were observed following the repeated administration. The results also suggest that possible binding of DTZ may occur at the site of injection when administered subcutaneously in the higher dose.

In order to identify a suitable rodent model for preclinical study of calcium antagonists, pharmacokinetics and metabolism of diltiazem (DTZ) were compared in normotensive SD and hypertensive SHR rat models following multiple doses (5 mg/kg twice daily for 5 doses). Plasma concentrations of DTZ and its major metabolites appeared to be higher in the SHR than the SD rats, although the differences did not reach statistical significance (p > 0.05). The preliminary results suggest metabolism profile of DTZ in the SHR may be closer to humans than the SD rats and may be more preferred in pre-clinical drug development studies for DTZ.

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.

AIMS To compare the pharmacokinetics and hemodynamic effect of diltiazem (DTZ) following single and repeated subcutaneous injection using an in vivo rat model. METHODS Male SD rats (n = 5 – 6 per group) weighing between 350 – 450g were used. Each rat received either a single 20 mg/kg dose of DTZ (Biovail Corp, Mississauga, Ont. Canada) by s.c. injection or 5 mg/kg s.c. bid for 5 doses. Plasma concentrations of DTZ and its major metabolites were determined by a previously published HPLC for up to 6h. In addition, hemodynamic measurements were recorded continuously for each animal during the experiment. RESULTS DTZ decreased SBP from 138 +/− 9 to 124 +/− 8 mmHg (10%) following the single dose and from 126 +/− 17 to 104 +/− 10 mm Hg (17%) following the 5th and last dose. The effects on DBP were also greater following the multiple doses (33% vs 26%), and the effects were also more sustainable after the repeated dosing. Plasma concentrations of DTZ were considerably higher after the single 20 mg/kg dose (AUC 8185 vs 3505 ng‐h/mL), although the half‐lives were longer at steady‐state (6 vs 2h). There were no apparent differences in the metabolite profiles. CONCLUSION Hemodynamic effects of DTZ were both qualitatively and quantitatively different between the single dose and steady‐state dosing. The reason is not completely clear although it may be related to greater tissue distribution of DTZ following repeated administration. (Supported in part by a grant‐in‐aid from CIHR/NSHRF/PEF Regional Partnership Program.) Clinical Pharmacology & Therapeutics (2005) 79, P53–P53; doi:

Although the differences were mainly quantitative and very small, the study has shown for the first time that the metabolism profiles of DTZ in SHR and WKY rats were closer to humans than SDR, and they may be more preferable rat models to study pharmacokinetic and metabolism studies of DTZ or similar agents.