Clinical Pharmacokinetics of Calcium Channel Antagonists

Pharmacokinetic data are important in the development of rational regimens for drug administration, particularly for agents with the potential for serious toxicity. Pharmacodynamic studies correlate drug dose and plasma concentration with observed effects (whether therapeutic or toxic) and aid in the establishment of appropriate dose ranges for desired drug activity. Verapamil is the only calcium channel antagonist for which detailed pharmacokinetic and pharmacodynamic data are available, and relatively few studies have been carried out in patients, in whom kinetic parameters are likely to differ from those found in normal subjects. Studies thus far indicate that verapamil is eliminated by hepatic metabolism, is subject to extensive first-pass extraction, and is characterized by cumulation during chronic oral administration. Plasma levels of verapamil appear to correlate well with both electrophysiologic and hemodynamic effects. Nifedipine pharmacokinetics are not well established and erratic absorption may be seen with the capsule presently available. Toxicity from overdosage appears to be less threatening than with verapamil. Diltiazem has been studied in a limited group of normal subjects, with considerable interindividual variation in plasma levels after fixed oral doses. This suggests that the drug is subject to first-pass elimination. The half-life appears to be approximately 5 h, but may increase as dose size is increased. For drugs with such broad therapeutic application as the calcium channel antagonists, the paucity of pharmacokinetic data is surprising. Further studies, particularly in patient subjects, are clearly needed.