The metabolism of nicardipine hydrochloride in healthy male volunteers

Abstract

Four human volunteers given a 30 mg oral dose of nicardipine hydrochloride containing 40 microCi of the 14C-labelled material achieved peak plasma levels of compound-related radioactivity within one hour of dosing. Parent compound comprised only a minor fraction of the circulating radioactivity indicating rapid first-pass metabolism. Plasma radioactivity declined to background levels within 96 h and was excreted both in the urine and faeces. Urinary excretion was the favoured route comprising about 60% of the dosed radioactivity. Mean total recovered radioactivity amounted to 94.8%. Both 1,4-dihydropyridine and pyridine metabolites of nicardipine hydrochloride were excreted in the urine. The major urinary metabolites, comprising some 36% of the radioactivity excreted in the 0-8 h post-dose period, were the glucuronide conjugates of +/- 2-hydroxyethyl methyl-1,4-dihydro-2,6-dimethyl-4(m-nitrophenyl)-3,5-pyridine dicarboxylate and its pyridine from 2-hydroxyethyl methyl-2,6-dimethyl-4-(m-nitrophenyl)-3,5-pyridine dicarboxylate.

Inhibitory effect of uraemia on the hepatic clearance and metabolism of nicardipine.

“…The overall correlation between the pharmacokinetic parameters, such as AUC, and the level of renal function suggests that the reduction in plasma clearance of nicardipine is related either directly to the deterioration in renal function (which is unlikely) or indirectly to the effects of renal dysfunction on hepatic metabolism. After oral administration nicardipine is subject to extensive hepatic metabolism (Higuchi et al, 1977;Rush et al, 1986) which may be saturable at relatively low concentrations (Graham et al, 1985;Seki & Takenaka, 1977). Thus the clearance of nicardipine ultimately depends on both liver blood flow and hepatocellular function.…”

“…In common with other calcium antagonist drugs, nicardipine undergoes extensive hepatic metabolism (Rush et al, 1986). Several pharmacologically inactive metabolites are produced 60% of which are excreted via bile and 40% excreted via urine, with less than 1% of the parent drug being eliminated unchanged by the kidney.…”

A Review on Barnidipine: A Novel Calcium Antagonist

“…In contrast with these compounds, the oxidation from pyridines may be less dominant for nicardipine (32) or nimodipine (l9), leading to the metabolites with an intact dihydropyridine nucleus. Since a dihydropyridine product (M-3) and its pyridine form (M-4) are major metabolites of barnidipine in human plasma, the primary metabolic pathways of barnidipine in humans is not only oxidation of the dihydropyridine ring but also hydrolysis of the side chain.…”

Microdose Clinical Trial: Quantitative Determination of Nicardipine and Prediction of Metabolites in Human Plasma

“…Nicardipine metabolites in the urine of animals and human have been investigated using 14 C-labeled nicardipine. [23][24][25] We hope to discover metabolites when a non-radioisotope labeled drug is administered to humans in a microdosing study. This should be an effective means for narrowing down to successful drug candidates.…”