Amlodipine Does Not Undergo Enterohepatic or Enteroenteric Circulation
Amlodipine does not undergo enterohepatic or enteroenteric circulation; it is eliminated primarily through hepatic metabolism with biliary excretion of metabolites, not unchanged drug, and renal excretion of these metabolites. 1, 2
Pharmacokinetic Profile and Elimination Pathways
The elimination of amlodipine follows a distinct pattern that excludes enterohepatic recirculation:
Hepatic metabolism is the primary clearance mechanism, with extensive oxidation to pyridine metabolites occurring in the liver, but notably there is no significant presystemic or first-pass metabolism despite extensive hepatic processing 1
Renal excretion is the major route of elimination, accounting for approximately 60% of the administered dose, with the majority excreted as metabolites rather than unchanged drug 2
Only 10% of urinary radioactivity represents unchanged amlodipine, with the remaining 90% consisting of pyridine metabolites formed through oxidation, oxidative deamination, de-esterification, and aliphatic hydroxylation 2
Biliary excretion accounts for the remainder of elimination (approximately 24% recovered in feces), but this represents metabolites, not intact drug that could be reabsorbed 2
Why Enterohepatic Circulation Does Not Occur
The chemical and pharmacokinetic properties of amlodipine prevent enterohepatic recirculation:
The drug undergoes complete metabolic transformation to pyridine derivatives that have minimal calcium antagonist activity, meaning any biliary-excreted material lacks pharmacologic activity and represents terminal elimination 2
Amlodipine's high degree of ionization at physiological pH (due to its positive ionic charge) contributes to its unique absorption and distribution characteristics, but this same property would limit reabsorption from the intestinal lumen if any intact drug were excreted in bile 3
The terminal elimination half-life of 40-50 hours reflects slow hepatic metabolism and large volume of distribution (21 L/kg), not recirculation; the even slower elimination of total drug-related material from plasma (up to 12 days for complete excretion) is consistent with metabolite formation and excretion, not drug recycling 1, 2
Clinical Implications
The absence of enterohepatic circulation contributes to amlodipine's favorable dosing characteristics:
Once-daily dosing is appropriate with relatively small peak-to-trough fluctuations at steady state, which is attributable to the long elimination half-life from slow hepatic metabolism rather than any recirculation mechanism 1, 3
No drug-drug interactions related to biliary excretion or intestinal reabsorption have been documented, though amlodipine is a substrate of intestinal P-glycoprotein (P-gp) for initial absorption 4