Phenytoin metabolism

Roy, D. and Snodgrass W.R. 1990. Covalent binding of phenytoin to protein and modulation of phenytoin metabolism by thiols in A/J mouse liver microsomes. J. Pharmacol. Exp. Ther. 252 895. 

Sulthiame (H7, 04), phcnacoraidc (H15), chloramphenicol (C5),dicou-marol (H6), antituberculous drugs (K23), disulfiram and phenyramidol (S23) have been described as inhibitors of phenytoin metabolism, while alcohol and possibly phenobarbitone have the reverse effect. Clinical and experimental evidence regarding the latter are confusing (B16, B29, C11,C12). 

High isoniazid plasma levels inhibit phenytoin metabolism and potentiate phenytoin toxicity when the two drugs are coadministered. The serum concentrations of phenytoin should be monitored, and the dose should be adjusted if necessary. 

The elimination of phenytoin is dose-dependent. At very low blood levels, phenytoin metabolism follows first-order kinetics. However, as blood levels rise within the therapeutic range, the maximum capacity of the liver to metabolize phenytoin is approached. Further increases in dosage, though relatively small, may produce very large changes in phenytoin concentrations (Figure 24-5). In such cases, the half-life of the drug increases markedly, steady state is not achieved in routine fashion (since the plasma level continues to rise), and patients quickly develop symptoms of toxicity. 

Phenytoin [NE] Decreased phenytoin metabolism increased serum phenytoin. 

Tricyclic antidepressants + phenytoin —> reduction in phenytoin metabolism can increase phenytoin toxicity. 

Houghton GW, Richens A. Inhibition of phenytoin metabolism by other drugs used in epilepsy. Int J Clin Pharmacol Biopharm 1975 12(l-2) 210-6. 

AMIODARONE ANTIEPILEPTICS-PHENYTOIN Phenytoin levels may be t by amiodarone conversely, amiodarone levels may be 1 by phenytoin Uncertain amiodarone inhibits CYP2C9, which plays a role in phenytoin metabolism while phenytoin is a known hepatic enzyme inducer. Also, amiodarone inhibits intestinal P-gp, which may T the bioavailability of phenytoin 1 phenytoin dose by 25-30% and monitor levels watch for amiodarone toxicity. Note that phenytoin and amiodarone share similar features of toxicity, such as arrhythmias and ataxia... 

Billings RE (1984b) Interactions between folate metabolism, phenytoin metabolism, and liver microsomal cytochrome P450. Drug Nutrient Interactions 3,21-32. 

May reduce phenytoin metabolism and increase phenytoin levels... 

Drugs that inhibit phenytoin metabolism (causing its plasma concentration to rise) include sodium valproate, cimetidine, co-trimoxazole, isoniazid, chloramphenicol, some NSAIDs, disulfiram. There is a considerable body of mediocre and contradictory data, the lesson of which is that possible interaction should be borne in mind wherever other drugs are prescribed to a patient taking phenytoin. 

Carbamazepine Phenytoin Interaction inconsistent and usually of limited clinical significance Induction and inhibition of phenytoin metabolism... 

Topiramate Phenytoin 2006 Elsevier B.V. All rights reserved. Interaction inconsistent, usually of little clinical significance Inhibition of phenytoin metabolism Continued... 

Ceftriaxone Phenytoin Risk of toxicity altered relation between total phenytoin concentration and effect Displacement of phenytoin from binding sites and possible inhibition phenytoin metabolism... 

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