ANTIEPILEPTIC DRUG METABOLISM IN ELDERLY USING STABLE ISOTOPES

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This project will characterize how advance age alters phenytoin and carbamazepine pharmacokinetics and metabolism. Specifically, this project will determine if the cytochrome P-450 isoenzymes (CYP2C9, CYP2C18, CYP2C19, and CYP3A4) responsible for metabolism of these drugs decline in the elderly. Complete characterization of antiepileptic drug (AED) pharmacokinetics and metabolism requires intravenous drug administration and intensive blood and urine sampling under steady-state conditions. This project will use an approach new to disposition studies in elderly patients: stable-labelled isotopes and chromatographic/mass spectrophotometry. Sixty elderly (greater than or equal to 65 years) men and women distributed among three age groups (young-old, old, and old-old) taking phenytoin will be recruited from participating clinics and nursing homes. The results from the sixty elderly will be compared to the results obtained from ten younger patients. The same approach will be used for carbamazepine. A small dose of stable phenytoin or carbamazepine labelled isotope will be administered intravenously and blood and urine samples will be collected over five days. Both total and unbound plasma drug and metabolite concentrations and urine drug and metabolite concentrations will be measured. Absolute bioavailability, free fraction, distribution volume, elimination half-life, and clearance will be calculated as will the contributions of CYP2C9, CYP2C18, CYP2C19, and CYP3A4 metabolic pathways to phenytoin or carbamazepine elimination. These results will be used to determine if the mechanism (s) for pharmacokinetic changes in the elderly are due to alterations in absorption, protein binding, or enzyme activity. Pharmacokinetic parameters obtained in elderly patients will be compared to those from younger patients. In addition, pharmacokinetic changes among the three elderly groups will be assessed by multivariant, regression analysis. Our results will be used to develop rational guidelines for dosage, dosing frequency, and monitoring of total and free drug levels.