Pharmacokinetics and Metabolism of Diltiazem in Rats: Comparing Single vs Repeated Subcutaneous Injections in vivo

摘要

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 20mg/kg dose of DTZ by subcutaneous (s.c.) injection or 5mg/kg s.c. twice daily for five doses. Plasma concentrations of DTZ and its major metabolites were determined by HPLC for up to 8h. 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 mug-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 1/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. Copyright ? 2007 John Wiley & Sons, Ltd.