CHRONOPHARMACOKINETICS OF DILTIAZEM

The chronopharmacokinetics of diltiazem were investigated after administration of a 60mg oral dose (immediate release capsule) at 4 different times over 24 hours (0600, 1200, 1800 and 2400h) to 8 healthy human volunteers in a randomised crossover study with a washout period of 1 week. Serum samples were analysed for unchanged diltiazem using high performance liquid chromatography. Pharmacokinetic parameters were calculated using model independent methods. A significant decrease in the C(max) (F = 6.52, p < 0.002) and AUC0-alpha (F = 3.26, p < 0.05) as well as an increase in the oral clearance (F = 3.62, p < 0.05) and apparent volume of distribution (F = 5.85, p < 0.01) were observed following administration at 0600h. Following the 2400h dose administration, the elimination half-life was significantly decreased as compared with that at the other dose times (F = 4.11, p < 0.025). These variations appear to be a result of time-dependent changes in the metabolism of diltiazem.