Effects of biliary excretion on the disposition of felodipine and metabolites in the rat

Abstract

1. After i.v. and intraduodenal administration of 3H-felodipine to rats, approx. 50% of the dose was excreted in bile in the first 6 h. Total urinary and biliary recoveries after both administration routes were similar. 2. Neither unchanged felodipine nor oxidized pyridine metabolite was detected in bile. Bile collection had no effect on the blood concentration-time profiles of either compound. 3. Bile collection decreased the area under the blood concentration-time curve (AUC) of total, unidentified felodipine metabolites by 30%, and their urinary recovery by 50%. 4. Of the total metabolites excreted in bile, 40% was calculated to be subject to enterohepatic recycling. 5. The dose-normalized AUC of both felodipine and pyridine metabolite were decreased after intraduodenal administration of drug, indicating pre-systemic elimination of drug, and possibly of the pyridine, in the gut. Route of administration had no effect on the AUC of total unidentified metabolites.

Biliary secretion of felodipine metabolites in man after intravenous [14C]felodipine

“…It has been shown that compounds with molecular weights between 350 and 450 can be extensively eliminated by the rat both in urine and bile [12], whereas the molecular weight threshold for biliary secretion may be higher in humans [13]. The behaviour of felodipine metabolites seems to correspond to this guideline, as studies in bile duct-cannulated rats showed that 50% of a single IV dose of [3H[felodipine was secreted as metabolites in bile in the first 6 h after dosing [3].…”

“…A. Sutfin et al: Biliary secretion of felodipine metabolites dose was secreted in bile, since the major proportion secreted by that route in the rat appeared there during the first 4-5 h after dosing [3].…”

“…Pooled intestinal aspirates from all 4 subjects were analysed for felodipine by liquid scintillation counting according to a method for urinary and biliary metabolite profiles [3]. Total 14C activity in plasma, urine and duodenal contents, and total 3H activity in duodenal contents, were measured by liquid scintillation counting.…”

“…Approximately 70% and 44% of a single dose of radiolabelled felodipine was excreted in urine by man and the rat over a 72 h period following administration. The corresponding amounts eliminated in the faeces, 10% and 57%, which presumably arise from biliary secretion, indicate a major species difference.Studies in rats with a bile duct cannula showed that 50% of a single, labelled dose was secreted in bile in the first 4 to 6 h after dosing [3]. Some Of this underwent enterohepatic recycling, which resulted in a higher blood concentration of total metabolites.…”