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Related Experiment Videos

Phenytoin intoxication during concurrent diazepam therapy.

H J Rogers, R A Haslam, J Longstreth

    Journal of Neurology, Neurosurgery, and Psychiatry
    |September 1, 1977
    PubMed
    Summary
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    Concurrent administration of diazepam significantly alters phenytoin metabolism, leading to potential intoxication. This interaction highlights the importance of careful drug monitoring in patients receiving phenytoin.

    Area of Science:

    • Pharmacokinetics
    • Drug Metabolism
    • Clinical Pharmacology

    Background:

    • Phenytoin elimination follows Michaelis-Menten kinetics, a saturable process.
    • Plasma phenytoin levels do not correlate linearly with dosage.
    • Concurrent drug administration can alter phenytoin's metabolic enzyme activity, impacting plasma levels.

    Observation:

    • Two cases of phenytoin intoxication occurred when co-administered with diazepam.
    • Intravenous phenytoin infusions were administered to assess pharmacokinetic parameters.
    • Apparent Michaelis-Menten constants (Km) and maximum velocity (Vmax) were computed.

    Findings:

    • In one patient, diazepam reduced Km from 50.3 to 0.8 μmol/l and Vmax from 4.4 to 1.3 μmol/l/hour.
    • In the second patient, diazepam reduced Km from 28.8 to 0.012 μmol/l while Vmax remained similar (0.92 vs 0.95 μmol/l/hour).

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  • These findings indicate diazepam significantly inhibits phenytoin metabolism.

    • Implications:

    • Concurrent use of diazepam with phenytoin can lead to supratherapeutic phenytoin levels and toxicity.
    • Clinicians must carefully monitor phenytoin concentrations when initiating or discontinuing diazepam.
    • Dosage adjustments may be necessary to prevent phenytoin intoxication in patients on concurrent therapy.