Stability of diltiazem and its metabolites in plasma during storage

Diltiazem (DTZ) is a calcium antagonist widely used in the treatment of angina and related heart diseases. It is extensively metabolized into a host of metabolites, some of which have potent pharmacological activities. Previous work has shown that DTZ and its major metabolite N-desmethyl-DTZ (MA) were unstable and readily decomposed to deacetyl-DTZ (M1) and deacetyl N-desmethyl-DTZ (M2), respectively. This report describes the stability of DTZ and its metabolites in plasma samples stored at±20 and±70°C for different periods up to 12 weeks. The results indicate that in those samples obtained from volunteers who received DTZ, no deterioration of DTZ or MA occurred up to 8 weeks, but considerable deterioration of DTZ to M1 and MA to M2 (p<0.01) occurred after 12 weeks. However, in samples prepared by adding DTZ and its metabolites to outdated plasma (spiked plasma), deterioration of DTZ occurred after 4–6 weeks of storage, but there were no concomitant increases in concentrations of M1 or M2. Thus, it appears that decomposition of DTZ and MA was affected by the nature of the plasma materials, but the reason for the differences in analyte stability observed between volunteers’ and spiked plasma is not known. Also, it appeared that DTZ and its metabolites in plasma samples stored at±70°C may be more stable than those at±20°C, although further studies are required to substantiate this observation. On the basis of these results, plasma samples obtained from patients or volunteers receiving DTZ should be analyzed within 8 weeks when the samples are stored frozen at±20°C.