STEADY-STATE PLASMA-CONCENTRATIONS OF DILTIAZEM AND ITS METABOLITES IN PATIENTS AND HEALTHY-VOLUNTEERS

Diltiazem (DTZ) is a calcium antagonist widely used in the treatment o f angina and hypertension. It is extensively metabolized in humans via N-demethylation, O-demethylation, deacetylation, and oxidative deamin ation, yielding a host of metabolites, some of which have potent pharm acological properties. After our initial identification of O-desmethyl DTZ (Mx) and N,O-didesmethyl DTZ (MB) as major metabolites of DTZ and our subsequent of identification of their chemical synthesis, an impr oved high-performance liquid chromatography assay was developed to det ermine the plasma concentrations of DTZ and seven of its major basic m etabolites, including the previously unquantitated Mr and MB. The syst em consisted of a C-18 analytical column protected by a C-18 cartridge guard column and a variable wavelength ultraviolet detector set at 23 7 nm. The mobile phase was a mixture of methanol, 0.04 M ammonium acet ate, and acetonitrile (38:36:26) containing 0.08% triethylamine, with final pH of the mobile phase adjusted to 7.5. The system was operated at room temperature isocratically at a flow rate of 1.2 ml/min. Using verapamil as an internal standard, DTZ and the basic metabolites in pl asma were determined in young healthy volunteers (n = 21) and in patie nts with ischemic heart disease (n = 19) at steady state after repeate d oral doses of 60 mg DTZ four times daily. Preliminary results show t hat steady-state plasma concentrations of DTZ and its metabolites were higher in the older patients than in young healthy subjects (p < 0.05 ).