Carbamazepine-10,11-epoxide (EPO) is one of the principal metabolites of the anticonvulsant carbamazepine (CBZ). Blood levels of EPO are routinely measureable in patients on CBZ therapy, but the majority of EPO is ultimately converted to carbamazepine-10,11-transdihydrodiol (DHD) by the enzyme system epoxide hydrolase (EH). Plasma EPO/CBZ ratios are reported to be higher in children than in adults, with ratios being highest in very young children. These findings imply that there are age-related changes in the development of EH with young children being relatively deficient in EH activity. Animal studies have shown that EH activity is low at birth and increases as the animal matures to adulthood. The stability of EPO allows it to be safely administered to human subjects, and therefore be used as a tool in measuring in vivo EH activity. We will administer isotopically labelled EPO to children on CBZ monotherapy in order to measure EH activity, and thereby determine the relationship between age and EH status in humans. If EH activity proves to be deficient in young children, an important implication is that children are more vulnerable to toxic effects of reactive epoxides which may be formed from drugs and environment pollutants.
