Phenytoin Exhibits Zero-Order Metabolism at High Doses
Phenytoin is the drug that demonstrates time-dependent zero-order (saturable) metabolism at high doses, transitioning from first-order kinetics at low concentrations to zero-order kinetics as hepatic enzyme capacity becomes saturated. 1, 2
Mechanism of Saturable Metabolism
Phenytoin undergoes hepatic metabolism via parahydroxylation by microsomal enzymes, a process that becomes saturated as serum concentrations approach therapeutic levels. 1 This saturation creates a nonlinear relationship between dose and steady-state serum concentration—once enzyme capacity is exceeded, small dose increases (50-100 mg) can produce disproportionately large increases in serum levels, carrying concentrations from the lower to upper therapeutic range. 1
The drug exhibits Michaelis-Menten pharmacokinetics rather than simple first-order elimination, meaning the rate of metabolism fails to increase proportionally with serum concentration once enzymes approach saturation. 1, 3 This saturable process is the hallmark of zero-order kinetics, where a constant amount (rather than constant fraction) of drug is eliminated per unit time. 2
Clinical Implications of Zero-Order Kinetics
The transition to zero-order metabolism makes phenytoin dosing extremely challenging within the therapeutic range, requiring careful titration and frequent serum level monitoring. 1, 3 The half-life becomes dose-dependent—less than 20 hours at low doses but progressively prolonged at higher doses as elimination pathways saturate. 4
In obese patients, the saturable kinetics become even more problematic, with some individuals requiring doses as high as 1000 mg daily to maintain therapeutic concentrations due to altered pharmacokinetic parameters. 3 The narrow dose range compatible with therapeutic (non-toxic) concentrations within individual patients makes monitoring essential. 2
Why Other Listed Drugs Do Not Exhibit This Property
- Warfarin: Metabolized primarily by CYP2C9 with first-order kinetics; drug interactions occur through enzyme inhibition/induction rather than saturation 5
- Lisinopril: Eliminated unchanged by the kidneys without significant metabolism [@General Medicine Knowledge]
- Gabapentin: Exhibits nonlinear pharmacokinetics due to saturable absorption (not metabolism), with renal elimination of unchanged drug [@3@]
- Lorazepam: Undergoes glucuronidation with first-order kinetics at therapeutic doses [@4@]
Common Pitfalls in Phenytoin Dosing
Avoid making standard linear dose adjustments when serum levels are near therapeutic range. 1 A nomogram-based approach accounts for the nonlinear relationship between dose increments and resulting serum concentrations. [@12@]
Monitor for phenytoin encephalopathy (cognitive impairment, cerebellar syndrome) which develops when saturation kinetics, individual metabolic differences, or drug interactions cause accumulation of unbound drug. [@11@] First-generation antiepileptic drugs like phenytoin are strong hepatic enzyme inducers, creating bidirectional interactions with many medications including chemotherapy agents. [@5@, 5]
In patients with renal failure, protein binding decreases, requiring lower target serum concentrations despite unchanged metabolism. [@15