PII-66Pharmacokinetics and hemodynamic effects of diltiazem in rats following single and repeated subcutaneous injection in vivo

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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: 10.1016/j.clpt.2005.12.191

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