Chronic and severe phenobarbital intoxication in a child treated with primidone and diphenylhydantoin

  • John T. Wilson
    Correspondence
    Reprint address: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tenn. 37232.
    Affiliations
    Division of Pediatric Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tenn. USA

    Division of Clinical Pharmacology, Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tenn. USA
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  • Grant R. Wilkinson
    Affiliations
    Division of Pediatric Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tenn. USA

    Division of Clinical Pharmacology, Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tenn. USA
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  • Author Footnotes
    * Recipient of a Research Career Development Award from the NIH (7 K04 HD 42,539).
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      Plasma levels of phenobarbital and diphenylhydantoin were followed in a 6-month-old infant chronically intoxicated with primidone. Extraordinarily high plasma levels of phenobarbital (202 μg per milliter) derived from primidone were found within one day after cessation of primidone therapy. This level of phenobarbital was not associated with respiratory depression, although marked sedation was noted. The plasma level of phenobarbital initially declined nonexponentially and then after five days exhibited a first-order decay: T 1/2=39 hours. Concomitant DPH plasma levels fell from 12 μg per milliliter, on admission, to a plateau of about 2 to 3 μg per milliliter on Day 6 through Day 17, and then rose to a new steady-state level of 4.5 to 6.5 μg per milliliter. These observations suggest that the elimination of phenobarbital may have been capacity limited by biotransformation processes at plasma levels above 70 μg per milliliter. The low levels of diphenylhydantoin (administered daily) associated with a decreased level of phenobarbital may have been mediated by prior induction of liver drug metabolic enzymes. Initially, however, high plasma levels of phenobarbital were associated with a higher level of diphenylhydantoin than would be expected for age or dosage, suggestive of inhibition of drug metabolism. Questions are raised about appropriate dosage and metabolic fate of primidone when used alone or with other anticonvulsants in young children.
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