The pharmacokinetic profile of amlodipine

Amlodipine, a dihydropyridine calcium antagonist, was synthesized in an attempt to develop a compound with a pharmacokinetic profile characteristic of this class, which would also have an increased oral bioavailability and extended clearance time. A single intravenous dose of 10 mg resulted in an absolute bioavailability of 64% and a calculated elimination half-life of 34 hours. The pharmacokinetic profile of oral doses showed similar changes. These results were significantly different from those seen with most other dihydropyridines (elimination half-life of 3 to 10 hours and absolute bioavailability of 10% to 30%) and nondihydropyridine calcium antagonists (elimination half-life 3 to 6 hours and low absolute bioavailability). With chronic oral dosing of amiodipine once daily for 14 days, support was provided for the linearity of amlodipine's pharmacokinetics and absence of such with chronic oral dosing with verapamil, diltiazem, and nifedipine. In the elderly population, elimination half-life of 5 mg oral doses is significantly prolonged (48 vs 35 hours; p < 0.025) suggesting decreased oral clearance or increased bioavailability. Comparison of the pharmacokinetics of amlodipine in patients with chronic stable angina pectoris with the profile in healthy volunteers suggested that clearance is not altered in patients with chronic stable angina, steady state being reached 6 to 12 hours after administration of the drug. In patients with cirrhosis, elimination half-life is significantly prolonged (60 vs 34 hours; p < 0.01) suggesting that there is a greater accumulation of amlodipine in patients with severe liver disease than in individuals with normal hepatic function. In patients with renal dysfunction such changes were not seen, suggesting that hepatic excretion is the dominant route. Neither food, digoxin (0.375 mg daily for 14 days), nor cimetidine (400 mg daily for 14 days) had any significant effect on the pharmacokinetic parameters determined for amlodipine. The results presented indicate that the pharmacokinetic profile of amlodipine is such that it is expected to be effective for the treatment of hypertension when administered once daily.