Phenytoin Excretion
Phenytoin is primarily eliminated through hepatic metabolism, with most of the drug excreted in bile as inactive metabolites that undergo enterohepatic recirculation before final urinary excretion; only 0.4-1.2% is excreted unchanged in urine. 1, 2
Primary Route of Elimination
Hepatic metabolism is the dominant pathway, with phenytoin undergoing hydroxylation in the liver by saturable enzyme systems to form 5-(4-hydroxyphenyl)-5-phenylhydantoin (4-OH-DPH), which is then conjugated with glucuronic acid 1, 3
The metabolic pathway is capacity-limited (saturable), meaning small dose increases can produce disproportionately large increases in serum levels when concentrations are in the upper therapeutic range 1
Most metabolites are excreted in bile, then reabsorbed from the intestinal tract and ultimately excreted in urine as inactive compounds 1
Renal Excretion (Minor Role)
Renal excretion of unchanged phenytoin is negligible, accounting for only 0.4-1.2% of the administered dose 2
Urinary excretion occurs partly through glomerular filtration but more importantly by tubular secretion 1
The conjugated metabolite (conjugated 4-OH-DPH) is eliminated renally with clearance close to glomerular filtration rate when corrected for protein binding, suggesting elimination by glomerular filtration only 2
In patients with renal failure, plasma concentrations of conjugated metabolites can accumulate to levels 10 times normal, though this does not significantly affect phenytoin itself 2
Clinical Implications for Elderly Patients
In elderly patients with pontine hemorrhage and hyperlipidemia, several factors require careful consideration:
Hyperlipidemia increases free phenytoin levels, particularly in hypercholesterolemia and mixed hyperlipidemia, elevating the risk of phenytoin toxicity and necessitating lower doses 4
Renal dysfunction does not require dose adjustment for phenytoin itself since hepatic metabolism is the primary elimination route, though elderly patients may have delayed excretion rates of some metabolites 5
The plasma half-life averages 22 hours (range 7-42 hours), with steady-state levels achieved after 7-10 days of therapy 1
Phenytoin is highly protein-bound, and free phenytoin levels may be altered in patients with abnormal protein binding characteristics, which can occur in elderly patients with multiple comorbidities 1
Important Monitoring Considerations
Therapeutic serum levels (10-20 mcg/mL) should be monitored, with trough levels obtained just prior to the next scheduled dose to assess compliance and effectiveness 1
Peak levels occur 4-12 hours after oral administration and help identify the threshold for dose-related side effects 1
In elderly patients with hyperlipidemia, closer monitoring is essential as elevated free phenytoin concentrations increase toxicity risk even when total serum levels appear therapeutic 4
Neonates and young infants have decreased protein binding leading to higher free phenytoin levels and increased toxicity risk, though this is less relevant for elderly patients 6