The metabolic fate of a drug can be influenced by several factors, including genetic polymorphisms in the enzymes involved in the metabolic pathways, the presence of other drugs that inhibit or induce metabolism, and the concentration of the drug. The last consideration is particularly important in overdoses, because some of the metabolic pathways that detoxify the drug may become saturated or conjugating cofactors may become depleted, leading to the accumulation of toxic metabolites that are produced only in insignificant amounts when the plasma concentration of the drug is below the toxicity threshold. A well-characterized example is the accumulation of a hepatotoxic intermediate in acetaminophen metabolism when the hepatic reserve of glutathione, which detoxifies the intermediate, is depleted by excess drug. Valproate is extensively conjugated to glucuronic acid, and more than half of an ingested dose is excreted in the urine as the glucuronide, along with smaller amounts of hydroxylated valproate metabolites and their glucuronide conjugates. Desaturation of valproate, ordinarily a minor pathway, may become clinically important at supratherapeutic concentrations of the drug. The 2-propyl-4-pentenoic acid (4-ene-) and 2-propyl-2,4-pentadienoic acid (2,4-diene-) metabolites are considered hepatotoxic. Whether the metabolites are neurotoxic has not been established.
Another consideration in assessing drug concentrations and toxicity associated with overdose is the fraction of drug bound to protein. At therapeutic plasma concentrations, >90% of valproic acid is bound to proteins, and this fraction is not pharmacologically active. The valproate binding sites on plasma proteins are easily saturable, however, and at plasma valproate concentrations modestly greater than the therapeutic maximum, the fraction of total valproate bound to protein starts to decrease. Therefore, an overdose may deliver a disproportionately greater amount of drug to tissues than therapeutic doses, producing rapidly escalating toxicity. A larger unbound fraction, however, should enhance removal of the drug from the blood by hemodialysis.
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Authors' Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.
- Received for publication June 9, 2011.
- Accepted for publication June 20, 2011.
- © 2011 The American Association for Clinical Chemistry