KEY WORDS Diltiazem Stability Plasma HPLC assay INTRODUCTION Diltiazem is a calcium antagonist which is currently used in the treatment of angina pectoris, hypertension, and supraventricular arrhythmias.'-4 At present, in our laboratory, diltiazem and six of its metabolites have been identified and quantified in human biological fluids either by gas chromatography' or high performance liquid chromatography.6 As a first biotransformation step, diltiazem may be either demethylated to MA (N-monodemethyldiltiazem) or deacetylated to DAD (desacetyldiltiazem). These two metabolites may undergo further biotransformation to M4 (O-demethyldesacetyldiltiazem), M2 (Ndemethyldesacetyldiltiazem) or M6 (N,O-didemethyldesacetyldiltiazem). The formation of DAD or M4 N-oxide intermediates may also occur. Despite the identification of these possible metabolites in humans, the pharmacokinetics of diltiazem are still poorly understood. Some authors reported that DAD was a major metab~lite,"~ while others have failed to detect any DAD'99p10 in the plasma of diltiazem-treated patients. This raised some concerns as to whether DAD is a true metabolite or a degradation product. In this regard, the differences observed in the concentrations of DAD could very well be dependent on the various specimen collection and analytical procedures used. The present article summarizes the results of stability studies on diltiazem and two of its