Rivastigmine Metabolism Pathway
Rivastigmine is rapidly and extensively metabolized primarily via cholinesterase-mediated hydrolysis to an inactive decarbamylated metabolite, with minimal involvement of cytochrome P450 enzymes. 1
Primary Metabolic Pathway
Rivastigmine undergoes enzymatic hydrolysis by esterases (specifically cholinesterase enzymes) at the site of action, converting it to a decarbamylated metabolite. 1 This is the predominant metabolic pathway and occurs rapidly after administration.
The decarbamylated metabolite is inactive and does not contribute to therapeutic effects. 1
This metabolism occurs at the site of action rather than through hepatic pathways, which is a unique characteristic distinguishing rivastigmine from other cholinesterase inhibitors like tacrine, donepezil, and galantamine. 1, 2
Minimal Hepatic Metabolism
Based on in vitro and animal studies, the major cytochrome P450 isozymes (CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, CYP2C19, and CYP2B6) are minimally involved in rivastigmine metabolism. 1
This lack of CYP450 involvement explains why rivastigmine has essentially no drug interactions related to cytochrome P450 enzymes in humans. 1
Elimination Pathway
The major pathway of elimination is renal, with 97% of radioactivity recovered in urine and only 0.4% in feces following administration of radiolabeled rivastigmine. 1
No parent drug is detected in urine—only metabolites are excreted. 1
The sulfate conjugate of the decarbamylated metabolite is the major component excreted in urine, representing 40% of the administered dose. 1
Mean oral clearance of rivastigmine is 1.8 ± 0.6 L/min after 6 mg twice daily dosing. 1
Clinical Implications of This Metabolic Pathway
The esterase-mediated metabolism and minimal CYP450 involvement make rivastigmine unlikely to have clinically significant drug-drug interactions with medications metabolized by hepatic enzymes. 1, 3
Population pharmacokinetic analysis demonstrated that rivastigmine pharmacokinetics were not influenced by commonly prescribed medications including antacids, antihypertensives, beta-blockers, calcium channel blockers, antidiabetics, NSAIDs, estrogens, salicylate analgesics, antianginals, and antihistamines. 1
No pharmacokinetic interactions were observed between oral rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in healthy volunteer studies. 1
The elimination half-life is approximately 1.5 hours, which is considerably shorter than other cholinesterase inhibitors like donepezil (70-80 hours). 1, 2
Important Pharmacokinetic Considerations
Rivastigmine has low protein binding (approximately 40%), which further reduces the potential for displacement interactions with other highly protein-bound drugs. 1, 4
The drug readily crosses the blood-brain barrier, reaching CSF peak concentrations in 1.4 to 2.6 hours. 1
Rivastigmine is classified as a pseudo-irreversible or intermediate-acting cholinesterase inhibitor because its inhibition of acetylcholinesterase lasts up to 10 hours, despite the short plasma half-life. 5, 4, 6 This prolonged enzyme inhibition occurs because the drug is metabolized at the site of action.