The Metabolism and Pharmacokinetics of Amlodipine in Humans and Animals

Abstract

Summary: 

The disposition of amlodipine, a new calciumchannel blocker with a slow onset and long duration of action, has been investigated in humans and in the animal species used in the evaluation of drug efficacy and safety. Pharmacokinetic studies were conducted with nonlabeled drug using specific high-pressure liquid chromatography or gas chromatographic procedures. The metabolic fate of the drug was investigated in mice, rats, dogs, and humans using [4-14C]-amlodipine. After intravenous administration, the percentages of the dosed radioactivity recovered in urine were 62% in humans, 45% in dogs, 38% in rats, and 25% in mice. The remainder of the doses were recovered in the feces. A similar pattern of excretion was observed after oral dosing indicating complete absorption of the 14C drug. Absorbed drug is extensively metabolized because only ∽5% of the dose was excreted unchanged in human urine. Metabolism in humans primarily involves oxidation to the pyridine derivative with subsequent oxidative deamination of the 2-aminoethoxymethyl side chain or deesterification at the 5-methoxycarbonyl group. These metabolites were common to either the rat or dog, although some dihydropyridine derivatives were observed as metabolites in these two species. None of the metabolites identified and then synthesized was found to have any significant calcium antagonist activity relative to amlodipine. Bioavailability of unchanged drug after oral administration was high with values of 63, 88, 100, and 100% in humans, dogs, mice, and rats, respectively. Mean plasma half-life values from single-dose studies were 35 h in humans (cf nifedipine, ∽2 h), 30 h in dogs, 3 h in rats, and 11 h in mice. Amlodipine is widely distributed in the body (volume of distribution = 21 L/kg in humans), which is the basis for the long half-life of the drug and its potential for once-daily dosing.