Pharmacokinetics and Metabolism of Diltiazem Following Multiple Doses:Comparing Normotensive Rat vs. Hypertensive Rat Models In vivo

Abstract

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.

Comparing pharmacokinetics and metabolism of diltiazem in normotensive Sprague Dawley and Wistar Kyoto rats vs. spontaneously hypertensive rats in vivo

“…Consistent with the results reported in previous studies (13,17,24,25) , the current study also indicates that M2 was the most abundant metabolite in the SDRs, followed by MA and M1 (see Table 1 ). While the plasma concentration-time profi les of the metabolites were similar (see Figure 1 ), MA was the most abundant metabolite in the SHRs and WKY rats, followed by M2 and M1 (see Table 1 ).…”

“…Although the plasma T ½ of MA appears considerably longer than DTZ, particularly in the SHRs (147.5 ± 139.9 vs. 4.11 ± 6.37 h), the difference was not statistically signifi cant (p > 0.05), see Table 1 . These data are consistent with the previous reports suggesting that the true T ½ of MA may be longer than DTZ (13,17) , although it will need to be confi rmed by injections of the metabolite directly.…”

“…As reported previously, the pharmacokinetics of Brought to you by | Western University Authenticated Download Date | 6/11/15 2:01 AM DTZ following subcutaneous injections estimated from eight sample time points collected over a period of 6 h could be adequately described by a two-compartment open model following intravenous bolus. The plasma concentration-time profi les of the metabolites could be characterized by a one-compartment open model following fi rst-order input (13,17,24,25) .…”

“…Previous studies have shown that the hemodynamic responses to DTZ were signifi cantly greater in spontaneously hypertensive rats (SHRs) and experimentally induced a higher renin rat model than in the SDR (11) (12) , and that plasma concentrations of DTZ and its active metabolites were also higher in the SHR (13) . Further, the metabolite profi les of SHR were also different from the SDRs as plasma concentrations of MA were higher than M2 and M1 in the SHR, whereas M2 was the most abundant metabolite in the SDRs (13) .…”