PHARMACOKINETIC ANALYSIS OF 2 NEW SUSTAINED-RELEASE PRODUCTS OF DILTIAZEM DESIGNED FOR TWICE-DAILY AND ONCE-DAILY TREATMENT

The pharmacokinetics of two new sustained-release (SR) products of dil tiazem, Dilapress 120 mg tablets and Dilapress 240 mg tablets, was ana lysed and characterized in three different studies, in comparison to t he following diltiazem SR formulations: Cardizem Retard, Cardizem SR, and Cardizem CD. Dilapress 120, designated for twice-daily dosing, was found to be bioequivalent to Cardizem SR and to Cardizem Retard with mean (+/- SD) relative bioavailability values of 99 +/- 27% and 113 +/ - 38%, respectively. Dilapress 240, designed for once-a-day treatment, was found to have a slower absorption rate than Cardizem SR and its e xtent of absorption was 56 +/- 19% relative to that of Cardizem SR. Ho wever, the bioavailability of Dilapress 240 relative to that of Cardiz em CD was 118 +/- 46%, indicating that the bioavailability of Cardizem CD relative to that of Cardizem SR was only 54 +/- 29%. Diltiazem is partially available due to a saturable liver first-pass effect. A high dose of Cardizem SR may partially escape this first-pass effect and, thus, achieve a higher extent of absorption than a slower SR product. Consequently, SR products of diltiazem designed for once-daily treatme nt may not reach the saturation stage in the liver first-pass effect p rocess that diltiazem is susceptible to. Consequently, a twice-daily S R product of diltiazem cannot serve as a reference for extent of absor ption assessments of a once-daily SR product.