Etomidate Metabolism and Excretion
Etomidate is rapidly metabolized in the liver by hepatic esterases through hydrolysis into an inactive carboxylic acid metabolite, with approximately 75% of the administered dose excreted in the urine during the first day after injection. 1
Hepatic Metabolism
- Etomidate undergoes rapid hepatic metabolism via esterase-mediated hydrolysis, converting the drug to R-(+)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid, which is pharmacologically inactive 1
- This carboxylic acid metabolite accounts for approximately 80% of urinary excretion 1
- The metabolic process occurs primarily through hepatic esterases, with some contribution from plasma esterases 2
- Metabolism follows capacity-limited Michaelis-Menten kinetics in the liver, meaning the metabolic pathway can become saturated at higher doses 2
Pharmacokinetic Profile
- Etomidate exhibits a three-compartment pharmacokinetic model with an initial rapid distribution phase (half-life approximately 2.6 minutes), an intermediate phase (half-life approximately 20 minutes), and a terminal elimination half-life of approximately 75 minutes 1, 3
- Minimal anesthetic plasma levels (≥0.23 mcg/mL) decrease rapidly within the first 30 minutes, followed by slower decline 1
- The drug is highly lipophilic with an octanol/water partition coefficient of 1000, facilitating rapid tissue distribution 3
Renal Excretion
- Approximately 75% of the administered dose is excreted in urine within the first 24 hours after injection, predominantly as the inactive carboxylic acid metabolite 1
- Unlike drugs such as amantadine that are excreted unchanged in urine, etomidate undergoes extensive metabolism before renal elimination 4
- The kidney serves as the primary route of excretion for metabolites rather than unchanged drug 5
Special Populations
Hepatic Dysfunction
- Patients with cirrhosis and esophageal varices demonstrate approximately double the volume of distribution and elimination half-life compared to healthy subjects 1
- Decreased metabolic clearance occurs due to impaired hepatic esterase function 3
Elderly Patients
- Elderly patients show decreased initial distribution volumes and reduced total clearance of etomidate 1
- Protein binding to serum albumin is significantly decreased in elderly individuals 1
- Clearance decreases by approximately 2 mL/min/kg per decade of age 3
Clinical Implications
- The rapid hepatic metabolism and short redistribution half-life account for etomidate's brief duration of hypnotic action, making it suitable for induction but not prolonged infusion 6
- Renal dose adjustments are generally not required since the drug is primarily hepatically metabolized rather than renally excreted unchanged, unlike medications such as amantadine 4
- Hepatic dose adjustments should be considered in patients with severe liver dysfunction due to prolonged elimination half-life and reduced clearance 1