Age-related changes in hepatic drug-oxidizing activity using trimethadione as a probe drug in human

Abstract

Objective: The purpose of this study was to examine the changes in trimethadione (TMO) metabolism over seven stages from neonates to elderly adults. Methods: The subjects were divided into seven groups according to age: neonates (<4 weeks; n=5), infants (<12 months; n=12), children (<10 years; n=21), adolescents (<20 years; n=3), young adults (<40 years; n=20), mature adults (<65 years; n=20) and elderly adults (⩾65 years; n=40). The metabolism of TMO following oral administration (4 mg/kg) was studied in 21 healthy volunteers and 100 patients. Results: The serum albumin, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were always within normal ranges. The serum dimethadione (DMO) versus TMO ratio (DMO/TMO) at 4 h after administration of TMO was low in neonates (mean±S.E.M.: 0.12±0.01). In infants, however, it reached approximately 95% of the peak observed in adolescents (0.64±0.09), and gradually decreased thereafter. Conclusion: These findings indicate that the metabolic rate of TMO varies according to the stage in life. Using TMO as a probe drug may be of value in determining changes in overall hepatic drug-oxidizing activity throughout the human life-span, thereby allowing evaluation of drug–drug interactions and clinically significant risks associated with drug therapy.