Combination treatment of epilepsy with ketogenic diet and concurrent pharmacological inhibition of cytochrome P450 2E1

Abstract

While most epileptic patients respond to treatment with existing antiepileptic drugs, there remains a considerable number of patients in whom these drugs do not suffice. Such patients, particularly children, are often treated using the ketogenic diet. This diet imposes a strict limit on carbohydrates; while providing for adequate protein, most of the calories are supplied as triacylglycerol, much of which is metabolized to ketone bodies. Animal experiments have provided evidence that the anticonvulsant effect of the ketogenic diet is mediated by acetone and correlates with blood acetone levels. Acetone can be converted in vivo to glucose via acetol and pyruvate; the initial conversion to acetol is catalyzed by cytochrome P450 2E1 (CYP2E1). When CYP2E1 knockout mice are subjected to starvation to induce ketogenesis, they develop blood acetone levels much higher than those observed in wild-type mice. Similarly, pharmacological inhibition of CYP2E1 significantly increases blood acetone levels in rat and man. Taken together, these observations suggest that pharmacological inhibition of CYP2E1 has the potential to significantly increase the antiepileptic effect of the ketogenic diet. With patients that respond insufficiently to the diet alone, increased acetone levels may improve response. With patients who respond sufficiently to the diet, CYP2E1 inhibitors might allow a relaxation of the fairly severe diet regimen and so improve compliance and quality of life. An existing inhibitor of CYP2E1 is the drug disulfiram. This drug also inhibits the enzyme aldehyde dehydrogenase, which functions in alcohol degradation, and in this capacity has long been used in the treatment of alcohol addiction. Disulfiram inhibits CYP2E1 at conventional therapeutic dosages and increases blood acetone levels in humans and animals. It should therefore be a viable candidate for the proposed drug/diet combination treatment.